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. 2011 Sep 28;69(5):727–740. doi: 10.1007/s00018-011-0839-7

Haploinsufficiency in mouse models of DNA repair deficiency: modifiers of penetrance

Diane C Cabelof 1,
PMCID: PMC11114761  PMID: 21952828

Abstract

Mouse models of DNA repair deficiency are useful tools for determining susceptibility to disease. Cancer predisposition and premature aging are commonly impacted by deficiencies in DNA repair, presumably as a function of reduced genomic fitness. In this review, a comprehensive analysis of all DNA repair mutant mouse models has been completed in order to assess the importance of haploinsufficiency for these genes. This analysis brings to light a clear role for haploinsufficiency in disease predisposition. Unfortunately, much of the data on heterozygous models are buried or underinvestigated. In light of a better understanding that the role of DNA repair haploinsufficiency may play in penetrance of other oncogenic or disease causing factors, it may be in the interest of human health and disease prevention to further investigate the phenotypes in many of these mouse models.

Keywords: Haploinsufficiency, DNA repair, Heterozygosity, Penetrance

Introduction

Loss of genomic stability increases risk for human diseases. It was the study of human disorders associated with increased cancer risk and premature aging that led to the discovery of many genes responsible for genome maintenance. These discoveries have driven the study of DNA repair, leading to the elucidation of multiple DNA repair pathways. Analysis of rare or familial cancer predisposition and/or aging syndromes has resulted in identification of genes responsible for the following syndromes: xeroderma pigmentosum, trichothiodystrophy, Cockayne syndrome, severe combined immunodeficiency, Werner syndrome, ataxia telangiectasia, Nijmegen breakage syndrome, Bloom syndrome, Rothmund-Thomson syndrome, breast cancer susceptibility, hereditary non-polyposis colorectal cancer (HNPCC), and Fanconi anemia (reviewed in [13]). Many of these syndromes also display phenotypes distinct from cancer and aging. These include photosensitivity, neurodegeneration, growth retardation, immunodeficiency, microcephaly, arteriosclerosis, diabetes mellitus, and skeletal defects [1, 2], demonstrating that repair deficiency increases risk for a variety of human diseases in addition to cancer and aberrant aging. The objective of this review is to evaluate the impact that haploinsufficiency for genes directly associated with DNA repair can exert on disease predisposition. The implications of this are expanded through consideration of conditions of genomic instability not yet directly associated with specific DNA repair pathways, as occurred with the discoveries of the XP and FANC genes. For example, copy number variations are increasingly associated with developmental delay [4], but the underlying source of these structural variations is not well understood. Further investigation into the DNA repair mechanisms that permit formation of and/or tolerance to these structural variations may elucidate additional links between DNA repair and a broad range of developmental diseases.

“DNA repair” is a term used here to describe mechanisms by which the cell responds to DNA damage by either repairing or tolerating DNA damage. In response to DNA damage, some mechanisms function to restore the original DNA sequence (base excision repair, nucleotide excision repair, mismatch repair, and direct reversal of damage); some mechanisms function to resolve DNA strand breaks (non-homologous end-joining, homologous recombination, single strand break repair); and some mechanisms function to permit tolerance to DNA damage and thereby survival. None of the tolerance models display haploinsufficiency and will not be discussed. A working model for the role of DNA repair deficiency in disease predisposition is that persistent DNA damage becomes fixed throughout the genome, promoting genomic instability through altered or reduced gene function. Consistent with this model, loss of DNA repair capacity exerts pleiotropic effects. Total loss of critical DNA repair proteins is often inconsistent with life, but partial loss can result in haploinsufficiency. In mouse models, genetically engineered heterozygosity typically induces phenotypes that are not apparent in the absence of additional disease-modifying factors, characterizing them as conditional haploinsufficiencies. As reviewed in Bartek et al. [5], conditional haploinsufficiency in DNA damage response genes may predispose to malignancy by modifying the penetrance of oncogenic events, primarily as a function of an altered DNA damage threshold. To broaden this concept, haploinsufficiency in DNA repair genes may predispose to human disease by modifying the penetrance of a variety of predisposing factors, including genetics, environmental exposures, and nutrient availability. Consistent with this is the suggestion that even moderate loss of genome maintenance can impact phenotype. Mouse models provide researchers the tools necessary to study the impact of gene dosage on disease risk and DNA damage sensitivity, including chemotherapeutic response.

Mouse models of DNA repair haploinsufficiency

The scope of this review is to evaluate the prevalence of haploinsufficiency in mouse models of DNA repair deficiency. For in-depth explanation of these repair pathways, the reader is referred to comprehensive reviews throughout the text. In addition, the databases listed below provide excellent resources for each repair mechanism. Haploinsufficiency is identified here as any impact of allelic insufficiency on phenotypic expression. In an attempt to identify all heterozygous mouse models of DNA repair deficiency, three primary databases have been used and cross-referenced. The UT Southwestern Medical Center’s Mouse Mutation Database (http://pathcuric1.swmed.edu/Research/research.htm) was used to identify mouse models of DNA repair mutants. Mouse mutants for all DNA repair genes within canonical repair pathways were assessed: base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination (HR), non-homologous end-joining (NHEJ), direct reversal, and genes related to human DNA repair deficiency diseases. As a secondary measure, the “Human DNA Repair Gene” list established by Wood, Mitchell, and Lindahl was used (http://sciencepark.mdanderson.org/labs/wood/DNA_Repair_Genes.html) to identify human genes and the mouse homologues that may not have been included in the UT Southwestern Medical Center database. Finally, using NCBI’s PubMed (http://www.ncbi.nlm.nih.gov/pubmed/), a search for “haploinsufficiency AND [gene name]” for each gene identified by the first two databases was conducted. In total, this search generated 125 gene-targeted DNA repair papers, and 44 of these papers presented data in the heterozygous models. Often when the null mutant is viable the heterozygous model is under-investigated, and therefore phenotypes associated with allelic insufficiency may exist but have not been elucidated. Likewise, data on the heterozygous models are occasionally only available in tissue culture models (mouse embryonic fibroblasts, embryonic stem cells, and lung embryonic fibroblasts, for example), and not in whole animal systems. As such, these data can be used to establish haploinsufficiency, but not to directly establish disease risk. Therefore, this review primarily reports data from whole animal models, but does make reference to some tissue culture data when that is all that is available in the literature. Another complication of these studies is that by virtue of Mendelian birth ratios of heterozygote/heterozygote crosses, heterozygous animals are occasionally used as “wild-type” controls, making it impossible to establish phenotypic differences between heterozygous and wild-type animals. Finally, the distinction between genes directly involved versus indirectly involved in DNA repair can become ambiguous, but an attempt has been made to restrict analysis to those genes directly involved in DNA repair.

For each of the following pathways, summary data can be found in tabular format with further explanation of these data being provided in the text. Mouse mutant papers in which no heterozygous data were presented are not included in this referencing.

Base excision repair

The base excision repair (BER) pathway is responsible for repair of DNA damage arising from spontaneous alkylation, oxidation, deamination, and depurination/depyrimidination events. BER also repairs these same damages that may be induced in response to chemical exposures (reviewed in [6, 7]). Consistent with the predominance of these types of DNA damage, BER is estimated to repair over 1 million nucleotides/cell/day [8]. The overall importance of BER in maintaining genomic stability and preserving embryonic fitness is evidenced in the lethality induced by homozygous deletion of the core BER genes. The BER core genes that are embryonic lethal include: DNA polymerase β (β-pol), Apex1, Xrcc1, Ligase1, and Fen1. Evidence is presented for haploinsufficiency in β-pol, Apex1, and Xrcc1 heterozygous models (Table 1, and discussed below). For Ligase1 and Fen1, no meaningful data on the heterozygous models have been presented in the literature, suggesting that perhaps haploinsufficiency has not been fully investigated in these models. Viable BER homozygous mutant models include: Parp, Myh, Aag, Polλ, Ung, Nth1, and Ogg1. For these models, data from the heterozygous models are presented for Aag, Nth1, Ogg1, and Parp. Of these there is evidence for haploinsufficiency for Aag, Nth1, and Ogg1. For Polλ, Ung and Myh, no data for the heterozygous models are presented. For Parp it appears the heterozygous mouse model presents no phenotype distinct from wild type, though MEFs from the heterozygous mice display haploinsufficiency for Parp activity and chromosomal stability [9]. In total, 26 BER mutant mouse model papers have been analyzed. Of these, 17 demonstrated haploinsufficiency in the following genes: β-pol, Apex1, Xrcc1, Aag, Nth1, and Ogg1.

Table 1.

Base excision repair

Gene −/−Lethal? Heterozygous phenotype References
Polβ Yes [27] Single strand break accumulation in response to acute oxidative stress; increased LacI mutation frequency in response to DMS; increased spontaneous chromosomal aberrations, specifically centromere separation [10]
Heterozygosity intensifies the single strand break phenotype induced by folate depletion [13]
Accelerated rate of aging; age-dependent lymphoma incidence increased sevenfold; twofold increase in hypoploidy in lymphcytes. [15]
Twofold increase in LacI mutagenicity in spermatogenic cells [11]
Heterozygosity results in two-fold increase in DMH-induced aberrant crypt foci (ACF). When dietary folate is restricted, wild-type mice accumulate ACF, but heterozygous mice appear to be protected. DMH induces liver tumors in the heterozygous mice, not in the wild-type mice, and not in the folate-restricted heterozygous mice. Heterozygous mouse has reduced apoptosis in response to DMH, but when folate is depleted apoptosis in the heterozygous mouse increases fivefold [14]
Conditional targeting to delete Polβ in sperm; both heterozygous and homozygous deletions result in increased lambda cII mutation frequencies; G > T and A > T mutations unique to heterozygous mice [12]
Apex1 Yes [17] Sensitivity to oxidative stress; reduced survival of pups and embryos; increased incidence of papillary adenocarcinoma and lymphoma [17]
Increased LacI mutagenicity in 3 months old liver and spleen and in 9 months old spermatogenic cells [18]
Appear to exhibit increased apoptotic response to acute oxidative stress [19]
Double mutant Apex1+/−/XPC−/−: p53-dependent modifier of penetrance for UV induced skin cancer [20]
XrccI Yes [28] Similar to wild-type phenotype in absence of challenge, though there are mild organ abnormalities; increased liver toxicity and ACF formation following AOM exposure, very similar to Polβ phenotype in response to DMH (metabolite of AOM) [21]
Hypomorph: Xrcc1 transgene-complemented null mice. Expression of as little as 10% of transgene permitted embryonic survival as well as growth to adulthood and normal fertility. No differential alkylation sensitivity [29]
Hypomorphs exhibit 25% reduction in body weight (decreased body fat) with no differential intake; metabolic effect potentially similar to caloric restriction [22]
Aag No [30] Retinal degeneration [23]
Nth1 No [25, 26] Sensitivity to acute oxidative stress is very similar between heterozygous and null mutants, as are thymine glycol and urea accumulation; wild-type data not presented for comparison to heterozygous mouse [25]
ES cells from heterozygous and null animals demonstrated a gene-dosage effect on Nth1 activity as het exhibits a 35% reduction below wild type in activity and null cells exhibit no activity [26]
Ogg1 No [24] 8oxoG:T, 8-oxo and faPy cleavage all reduced in manner consistent with gene-dosage [24]

β-Pol heterozygous model

Young, unexposed/unchallenged animals have a minimal phenotype [10], with the exception of spermatogenic cells in which a twofold increase in spontaneous LacI [11] and/or lambda cII mutagenicity [12] is observed. Other tissues show no increase in mutagenicity in the absence of a chemical challenge. However, in response to chemical exposure or aging, heterozygous loss of β-pol acts as a significant modifier of penetrance: increased mutagenesis in response to DMS [10]; accelerated strand break accumulation in response to oxidative stress [10] and folate depletion [13]; increased aberrant crypt formation (ACF) in response to DMH [14]; increased liver tumors in response to DMH [14]; accelerated spontaneous tumorigenesis (lymphoma and adenocarcinoma) [15]; and an accelerated rate of aging [15]. This model presents an interesting dichotomy with respect to risk (not unlike several of the other models reviewed, below), in that under some conditions (DMH exposure and aging) heterozygosity increases tumor risk and under other conditions it appears to reduce tumor risk. Under normal dietary conditions, β-pol heterozygosity increases the number of DMH-induced ACF, but when the B-vitamin folate is limiting in the diet, β-pol heterozygosity protects from these tumors. This appears to be due to a robust apoptotic response when folate is depleted in the heterozygous model, suggesting requirement of intact DNA damage responses [14]. This report is not unlike the protective effect of homozygous Ku80 deletion on APCmin tumorigenesis [16], which is a p53-dependent effect. The protective effect of β-pol heterozygosity on DMH-induced ACF likewise seems to be dependent on an intact p53 response as well, as the protective effect is lost in a p53+/− background (personal communication, Ahmad Heydari).

Apex1 heterozygous model

In this model, an effect on health in response to heterozygosity is seen early on as increased sensitivity to oxidative stress [17], increased spontaneous mutagenicity at 3 months (liver and spleen) or 9 months (spermatogenic cells) [18]. This is unlike the β-pol heterozygous model in which exposure was required to increase mutagenicity (with the exception of spermatogenic cells). Haploinsufficiency is further evidenced by increased development of lymphoma and adenocarcinoma [17] (as seen in the β-pol model as well). Evaluation of the oxidative stress response shows an increased apoptotic response to DNA damage [19], suggesting that heterozygous loss of Apex1 is also a modifier of penetrance. Further evidence for this is seen in the Xpc-null background where Apex1 does act as a modifier of penetrance for UV-induced skin cancer [20]. As described above for β-pol and Ku80, this effect is p53-dependent.

Xrcc1 heterozygous model

As with β-pol and Apex1, there is a definite phenotype in the Xrcc1 heterozygous model, and one remarkably similar to that seen in the β-pol model. Perhaps this is not surprising, considering the structural and functional involvement between the two proteins. Mice exposed to AOM (of which DMH is a metabolite) exhibit a twofold increase in ACF formation [21]. This is identical in the phenotype and magnitude of phenotype to that seen in colon of the β-pol heterozygous model, demonstrating that Xrcc1 is, likewise, a modifier of penetrance. The hypomorph Xrcc1 model (transgene-complemented null Xrcc1, with ~10% Xrcc1 expression) has a very unique phenotype with respect to metabolism. In spite of similar dietary intakes, the hypomorphs display a 25% reduction in body weight, primarily as a decrease in body fat [22]. It’s presently unclear what the mechanism for this metabolic abnormality may be, and is also unclear whether this would be a protective or detrimental effect. Experimental conditions that result in smaller sized animals often exert protective effects with respect to both longevity and cancer predisposition. Caloric restriction, for example, reduces body size, extends lifespan, and delays the onset and progression of cancer. As a potential caloric restriction mimetic, one could suggest the possibility of a protective mechanism in the XRCC1 heterozygote, but the increased ACF formation suggests the opposite. Again, it may be that under some conditions, heterozygosity is beneficial, and under others it is detrimental.

Glycosylase heterozygous models

There are not many data in the literature on heterozygous glycosylase models, primarily because the homozygous mutants are viable and are therefore typically the primary models under investigation. There are, however, some intriguing data suggesting haploinsufficiency for three glycosylases: Aag, Ogg1 and Nth1. In the Aag heterozygous model there is an increase in the rate of retinal degeneration [23], creating a definite link between haploinsufficiency and disease. In the Ogg1 heterozygous model, no disease-related phenotypes have been reported, but heterozygosity does result in reduced 8oxoG:T and formamidopyrimidine (FaPy) cleavage [24], providing evidence for repair haploinsufficiency as expected based on gene dosage. Though the Ogg1 data provide no direct link to disease, the allelic insufficiency vis-à-vis repair capacity might be anticipated to modify penetrance of diseases associated with oxidative stress (aging, Alzheimer’s disease, cancer, etc.). Unfortunately these questions have not been fully investigated. Nth1 heterozygous mice have DNA damage profiles and sensitivities very similar to the null mutants, though data from the wild-type animals is not shown so it is difficult to interpret the data [25]. In embryonic stem (ES) cells from wild-type, heterozygous and null mice, Nth1 excision activity is reduced 35% below wild-type activity [26] (zero activity in null ES cells). This is potentially interesting within the context of the roughly equal damage profiles between the heterozygous and null animals, suggesting that 65% residual activity in the heterozygous model is not adequate to resolve the DNA damage.

Nucleotide excision repair

In contrast to BER, nucleotide excision repair (NER) removes helix-distorting lesions from DNA (reviewed in [31, 32]). Much of the damage repaired by NER is induced by ultraviolet (UV) radiation or other environmental toxins that induce similar bulky lesions in the DNA. Human diseases traced to genetic defects in the ability to repair these types of DNA damage include Xeroderma pigmentosum, Cockayne syndrome and trichothiodytsrophy, and the genes involved in this repair are the complement of NER genes. The NER genes whose loss results in embryonic lethality include: Xpd, Ddb1, and Hr23b (90% of embryos die in utero). Xpa, Xpc, Csa, Csb, Ercc1, Xpg, and Xpf are all viable homozygous mutant models, though Ercc1, Xpg, and Xpf homozygotes die before weaning. In total, 15 NER mutant mouse model papers representing 11 NER genes have been analyzed. In ten of these papers the heterozygous models failed to exhibit any phenotype. In five of these papers representing three genes (Xpc, Xpa, and Ercc1) a phenotype was observed for the heterozygous models (Table 2).

Table 2.

Nucleotide excision repair

Gene −/−Lethal? Heterozygous phenotype Referencees
Xpc No [38] Increased predisposition to UVB radiation-induced skin cancers; heterozygosity accelerates p53-dependent cancers [33]
Increased LacZ mutagenesis in liver and spleen, intermediate between null and wild type; with age, mutagenicity increases three to fourfold more in heterozygous than in wild type in spleen and two to threefold more in heterozygous than in wild type in liver [34]
Xpa No [35] Appears to be a slight differences in survival in response to UV (but not DMBA) and an approximate 10% difference in the number of papillomas induced following DMBA as compared to wild type (in null mutant, it is a 60% difference from wild type) [35]
Ercc1 No, but died before weaning [36] Following UV exposure there appears to be a slight decrease in survival in the heterozygous mouse, though very mild compared to effect in null mutant. With increasing doses of UV, the heterozygous mice show a slight attenuation in incision activity (null mutants have essentially no incision acitivity) [36]
Ercc1−/m: one knockout allele, one mutant allele. This extends lifespan of the null mutant approximately 6 months; LacZ mutagenicity approximately threefold higher in liver compared to wild type [37]

Xpc heterozygous model

Xpc heterozygosity increases UVB radiation-induced skin cancers in a gene-dosage manner. Median survival following UVB irradiaion for the null model, heterozygous model and wild-type model is 25, 50, and nearly 100 weeks, respectively [33]. In addition, Xpc heterozygosity slightly accelerates UVB irradiation-induced skin cancers in p53 +/− mice and does so without promoting loss of heterozygosity (LOH) [33]. Oddly, Apex heterozygosity appears to modify this Xpc effect on skin tumors, once again suggesting that the specific experimental and genetic conditions are critical factors determining disease risk [33]. Uehara et al. investigated LacZ mutagenesis in liver, spleen, heart, and lung of the Xpc null and heterozygous models, and found that in liver and spleen there is a definite impact of heterozygosity on spontaneous, age-dependent mutagenesis [34]. While at weaning mutation levels are essentially identical in all three Xpc models, over time the differences from wild type grow such that by 24 months of age the mutation frequency in the heterozygous Xpc mice is three- to fourfold higher in spleen and two- to threefold higher in liver as compared to wild type. Thus, data presented for the Xpc heterozygote demonstrate not only a phenotype of increased disease risk (skin cancer), but also point to mechanism (mutation accumulation). This is not an unanticipated finding, but is rare in that only infrequently are heterozygous phenotypes investigated when the homozygous model is viable.

Xpa heterozygous model

The case for haploinsufficiency for Xpa is not very strong, but there is some evidence of a mild phenotype in the heterozygote. While unscheduled DNA synthesis (UDS) is not different between wild-type and heterozygous genotypes, mouse embryonic fibroblasts (MEFs) from these animals do exhibit very slight differences in UV sensitivity at high doses (wild-type and heterozygous survival diverges at 6 J m−2) [35]. Contrarily, survival in response to DMBA does not differ between the genotypes. In spite of no effect of genotype on survival in response to DMBA, there does appear to be a ~10% difference in DMBA-induced papilloma incidence between the wild-type and heterozygous genotypes [35].

Ercc1 heterozygous model

McWhir et al. show that MEFs from the Ercc1 heterozygous model have a slight decrease in survival following UV exposure, but nothing compared to the dramatic impact of homozygous loss on UV sensitivity. Interestingly, at low doses of UV exposure, wild-type and heterozygous MEFs exhibit similar incision activity (i.e., repair response), but as the UV dose increases, the heterozygous MEFs are not able to maintain the level of repair induced in wild-type MEFs [36]. In spite of this repair haploinsufficiency, there does not appear to be a difference in tumor formation between wild-type and heterozygous models in response to UVB irradiation [36]. These data suggest that the repair insufficiency may not extend to the critical disease phenotype. However, in the Ercc1 model in which one allele is disrupted and the other is mutated (Ercc1 −/m), LacZ mutation frequency is increased approximately threefold as compared to wild type [37], supporting the likelihood of haploinsufficiency for Ercc1 and a role for its haploinsufficiency in tumorigenesis.

Mismatch repair

Mismatch repair is the cell’s mechanism for resolving replication errors (reviewed in [39, 40]). Loss of the ability to repair mismatches results in a phenotype of microsatellite instability (MSI), strongly associated with HNPCC (hereditary non-polyposis colorectal cancer). In total, 19 mismatch repair knockout papers have been analyzed covering the following genes: Msh2, Mlh1, Pms1, Pms2, Msh6, Msh3, Msh4, and Msh5. The null mutant for each of these genes is viable. As such, several papers present no data at all on the heterozygous models, including Msh3, Msh4, Msh5, and Pms1. However six papers, representing Msh2, Mlh1, Pms2, and Msh6 do provide data on the heterozygous model and, accordingly support a role for haploinsufficiency within these genes (Table 3).

Table 3.

Mismatch repair

Gene −/−Lethal? Heterozygous phenotype References
Msh2 No [41] Double mutant: Msh/APCmin. Survival is similar between heterozygous and wild-type mice, but ~40% more tumors develop in the heterozygous model. Further, only about 10% of these display loss of residual MMR activity, suggesting LOH of the wild-type allele is not responsible for tumorigenesis in the heterozygous mice [42]
Mlh1 No [43, 48] Mismatch repair activity follows gene dosage: G:G mismatch repaired 50% less in heterozygote than in wild type but twofold greater in heterozygote compared to null mutant [43]
Gene dosage effect on both mean and maximum lifespan, with heterozygote falling between wild-type and null mutant; increased incidence of tumors (both gastrointestinal and extra-gastrointestinal) over wild type [44]
MNU-induced tumor data analyzed on Mgmt null background; Mlh1 heterozygous mice have fewer tumors than Mlh1 null mice; no Mlh1 wild-type data presented in order to determine whether Mlh1 heterozygosity is a modifier of penetrance [45]
Pms2 No [49] Increased intestinal adenomas in APCmin mouse in a gene dosage manner [46]
Msh6 No [47] Increased tumor incidence; haploinsufficiency for repair of 5′G:G, 3′C:A mispairs, and 1 and 4 nucleotide ins/del mismatches [47]

Msh 2 heterozygous model

De Wind et al. show no effect of Msh2 heterozygosity on tolerance to MNNG, suggesting that the heterozygous model might exhibit a wild-type phenotype [41]. In their later work, however, they demonstrate clearly that Msh2 is a strong modifier of penetrance in the APCmin model of intestinal tumorigenesis. While there was no difference in survival between the heterozygous and wild-type models in an APCmin background, approximately 40% more tumors developed in the Msh2 heterozygous animals as compared to the wild-type animals [42]. Further, only ~10% of these tumors exhibited loss of residual MMR [42], suggesting that loss of heterozygosity (LOH) was not the mechanism by which tumor incidence was accelerated by Msh2 heterozgyosity. These data strongly link allelic insufficiency for Msh2 with tumor incidence. These two reports reinforce the issue that baseline phenotypic differences between wild-type and heterozygous models are not always present, but that when challenged the loss of repair capacity can increase damage loads, mutagenesis, and tumorigenesis.

Mlh1 heterozygous model

Edelmann et al. clearly demonstrate that heterozygous loss of Mlh1 results in a loss of repair activity that follows a gene-dosage response. They show that G:G mismatch is repaired 50% less efficiently in the heterozygous animal than in the wild-type and twofold more than in the null mutant [43]. In a follow-up analysis of survival, they show a survival curve in which survival likewise follows gene-dosage, with a mean lifespan at approximately 6, 16, and over 24 months in the null, heterozygous and wild-type models, respectively [44]. This lifespan study did not continue on to evaluate maximum lifespan in the heterozygous and wild-type models (it was ~13 months in the null mutant), but the curves strongly suggest a significant difference in maximum lifespan as well. Further, there are more gastrointestinal and extra-gastrointestinal tumors in the heterozygous animals than in the wild-type animals. Interestingly, addition of the APC mutation did not impact the tumor profile of the Mlh1 heterozygous mouse, so it does not modify the penetrance of APC mutations [44]. Takagi et al. used lung embryonic fibroblasts from null and heterozygous Mlh1 animals and found that loss of Mlh1 rescued MNU killing in Mgmt mutant cells [45], another of the counterintuitive findings. The authors also investigated mutant frequencies and tumor formation in response to MNU on an Mgmt null background, but no Mlh1 wild-type controls were used, so the ability of Mlh1 to modify the impact of MNU under these conditions cannot be evaluated.

Pms2 heterozygous model

Baker et al. analyzed the impact of Pms2 on tumor formation in the APCmin model. They found that the number of intestinal ademonas in the APCmin mouse was 72, 90, abd 270 in the Pms2 wild-type, heterozygous and null models, respectively [46]. These data support haploinsufficiency for Pms2, again as a modifier of penetrance.

Msh6 heterozygous model

Edelmann et al. established an Msh6 mouse model in which they evaluated the impact of Msh6 gene dosage on repair capacity, survival, and tumor formation. There is clear haploinsufficiency for repair of G:G mismatches with the strand-specifying nick 5′ of the lesion, C:A mismatches with the nick 3′ of the lesion, and 1 and 4 nucleotide insertion/deletion mismatches [47]. In addition, survival curves suggest there may be subtle differences between wild-type and heterozygous models with respect to survival, but the curves were only extended to 16 months. This was well short of both the mean and maximum lifespans for wild-type and heterozygous mice, so no conclusions about lifespan in the heterozygous model can be drawn. However, there is a clear impact of heterozygosity on tumor development. By 20 months of age, no tumors had been identified in the wild-type animals. In the heterozygous animals NHL, carcinomas, microadenomas, B cell lymphomas, and dermatofibromas were identified, and had developed starting at about 8 months of age [47]. Clearly, heterozygous loss of Msh6 induces a cancer phenotype, supporting a role for Msh6 haploinsufficiency in disease risk.

Homologous recombination

Canonical homologous recombination (HR) is a pathway for repair of DNA double strand breaks that utilizes either the homologous chromosome or the sister chromatid to promote essentially error-free repair (reviewed in [50]). Permutations of HR such as non-allelic homologous recombination and/or break-induced replication may promote survival in response to double strand breaks at the expense of fidelity, and require further investigation in mammalian models. Gene-targeted mutants for core genes within the HR pathway have been developed for Rad52, Rad52, Rad51l1, Rad51l3, Rad50, Xrcc2, and Rad21. Biallelic disruption of Rad51, Rad51l1, Rad51l3, Rad50, Xrcc2, and Rad21 is embryonic lethal. The original papers describing Rad51, Rad52, and Rad50 do not present any data on the heterozygous models. The original papers describing Rad51l1 and Rad51l3 present data on the heterozygous models, but identify no phenotypes associated with monoallelic disruption of the genes. Only Rad21 and Xrcc2 mutations generated heterozygous data consistent with haploinsufficiency (Table 4). In total, 14 papers were analyzed, and only 2 of these papers support haploinsufficiency for HR, keeping in mind that phenotypes in heterozygous models were not investigated for most of the HR mutants (Table 5).

Table 4.

Homologous recombination

Gene −/−lethal? Heterozygous phenotype References
Rad21 Yes [51] Reduced homologous recombination and sister chromatid exchange (SCE); increased whole body IR sensitivity; gastrointestinal hypersensitivity to IR; bone marrow stem cell clonogenic regeneration reduced [51]
Xrcc2 Yes [52] Double mutant APCmin/Xrcc2. Xrcc2 heterozygosity protects from spontaneous tumorigenesis but increases IR-induced tumors; heterozygosity increases LOH [53]

Table 5.

Non-homologous end-joining

Gene −/−Lethal? Heterozygous phenotype References
Ku70 No [55, 57] Data in mouse embryonic fibroblasts (MEFs) only. Looks like there may be a trend towards an impact of heterozygosity on senescence and cell cycle regulation [55]
DNA-PKcs No [56, 58] Data in MEFs only. Looks like there may be a slight increase in IR sensitivity [57]

Rad21 heterozygous mutant

Homozygous loss of Rad21 is lethal [51], but the heterozygous model has been well characterized. The heterozygous model exhibits reduced HR and SCE (sister chromatid exchange) [51], demonstrating haploinsufficiency for repair capacity and suggesting increased disease risk in response to exposures that induce DNA double strand breaks. In support, the heterozygous mice are more sensitive to whole body irradiation, and they experience gastrointestinal hypersensitivity in response to ionizing radiation [51]. Not only do these data suggest increased cancer risk, they also point to important clinical considerations for haploinsufficient individuals undergoing radiation treatment. These animals also display impaired bone marrow stem cell regeneration [51].

Xrcc2 heterozygous mutant

Deans et al. established ES cells from Xrcc2 wild-type, heterozygous and homozygous embryos, and found no difference between wild-type and heterozygous cells with respect to either gamma-irradiation sensitivity or chromosomal aberrations [52], suggesting a lack of haploinsufficiency for Xrcc2. However, when crossed with the APCmin mouse model, Haines et al. found that Xrcc2 modifies the impact of APC mutagenesis [53]. These data are interesting, though not inconsistent with the above described studies, in that the effect of Xrcc2 gene dosage (i.e., protective or detrimental) depends upon the specific experimental conditions. Xrcc2 heterozygosity protects from the spontaneous intestinal tumorigenesis induced by the APC mutation, but enhances IR-induced tumorigenicity in this same APC model [53]. It is difficult to reconcile such data without further experimental evidence. It is important to note that heterozygosity does increase LOH, so the phenotypes observed may not be due to haploinsufficiency.

Non-homologous end-joining

Non-homologous end-joining (NHEJ) and HR work in coordination through the cell cycle to resolve DNA double strand breaks (reviewed in [50]). Loss of NHEJ results in immunodeficiency as a function of its critical role in V(D)J recombination (reviewed in [54]). NHEJ functions to repair DNA double strand breaks arising in response to exposure during resting and early synthesis phases of the cell cycle (when sister chromatids are not available for use as repair templates), and during maturation of B and T lymphocytes. Mice with targeted deletions in Ku80, Ku70, Ligase IV, Xrcc4, and DNA-PKcs have been developed, as well as a combined Ku80/Ku70 model. Of these, Ligase IV and Xrcc4 are embryonic lethal. The null models exhibit the following phenotypes: severe immune deficiency, exhibiting aberrant formation of coding joints and/or signal joint formation, inability to form mature B cells, and/or inability to conduct V(D)J recombination; double strand break repair deficiency; and severely runted size. In nearly all these models the heterozygous models are used as the control against the null mutants. This makes it impossible to identify phenotypes in the heterozygous model distinct from wild-type models. In total, 12 gene-targeting papers have been analyzed, and in only 2 of these studies is there even a slight indication that the heterozygous models may exhibit a phenotype. At that, these data are only presented for the MEFs derived from the Ku70 and DNA-PKcs embryos. The data in these papers suggest, at best, only a very mild phenotype in the heterozygous cells.

Ku70 heterozygous model

While the null mutant MEFs exhibit a robust early senescence phenotype, data in the heterozygous MEFs suggest a mild senescence phenotype relative to the wild-type cells [55]. There may also be subtle differences in cell cycle regulation in the heterozygous cells, but it is not possible to quantify or evaluate statistical significance. This does not rule out the possibility of haploinsufficiency for Ku70, but does indicate that more robust assessment would be necessary to establish this impact.

DNA-PKcs heterozygous model

As with the Ku70 MEFs, there is no dominant phenotype apparent in the DNA-PKcs heterozygous cells. There may be a slightly increased IR sensitivity [56], but as above, it is not possible to evaluate the statistical significance of this observation.

Direct reversal

Direct reversal is a mechanism for repairing DNA damage without compromising the phosphodiester backbone (reviewed in [59]). In direct reversal a suicide enzyme transfers the alkyl group (i.e., the damage) on the DNA base to its own cysteine residue, all without disrupting the DNA structure. There are very few genes with these specificities, and they include O 6-methylguanine DNA-methyltransferase (Mgmt) and the AlkB homologues. Mgmt removes alkylation damage to guanine and thymine, thus preventing mispairing and mutation fixation that could arise during replication over the damaged bases. The AlkB homologues directly remove 1-methyladenine and 3-methylcytosine from the DNA. There are four mouse models for direct reversal, and biallelic loss is tolerated in all four (Mgmt, mAlkb1, mAlkb2, mAlkb3), though the mAlkb1 model exhibits skewed Mendelian ratios. Two of the four papers presented no data on the heterozygous models, while two present evidence of haploinsufficiency for both Mgmt and mAlkb1 (Table 6).

Table 6.

Direct reversal

Gene −/−Lethal? Heterozygous phenotype References
Mgmt No [61] MEFs only. Methyltransferase activity consistent with gene dosage; sensitivity to BCNU, MNNG, STZ, and temozolomide follow gene dosage, with heterozygous mutant cells intermediate between wild-type and null mutant sensitivities [59]
Alkb1 No [62] One female born to every 3-4 male pups in heterozygous and null mutants; both heterozygous and null mutants display exencephaly, but phenotype in heterozygote is milder [60]

Mgmt heterozygous model

Data presented from liver tissue, ES cells, and MEFs from the wild-type, heterozygous, and null Mgmt models clearly demonstrate a gene dosage effect on methyltransferase activity [59], establishing haploinsufficiency for repair capacity. In addition, the MEFs are sensitive to BCNU, MNNG, STZ, and temozolomide in a gene-dosage manner [59], such that allelic insufficiency for Mgmt would be anticipated to modify risk in response to environmental exposure.

mAlkb1 heterozygous model

Both heterozygous and null mAlkb1 models are born at reduced Mendelian ratios with a strong sex selection against females [60]. Both mutants exhibit exencephaly, evident at E14.5, but the extent of exencephaly and the extent of runting in the null model are substantially more severe than in the heterozygous model [60]. This establishes that haploinsufficiency exists and that gene dosage has an important impact on severity of phenotype.

DNA repair genes associated with human disease

Several genes have been identified as repair genes by virtue of their association with DNA damage intolerance as a phenotype of specific human diseases. These include the BRCA genes, the Fanconi anemia genes, the helicases associated with Werner, Bloom, and Rothmund-Thomson syndromes, as well as genes associated with ataxia telengiectasia. Thirty-seven papers reporting on gene-targeted mutations for the following genes were reviewed: Brca1, Brca2, Fanca, Fancc, Fancd2, Fancg, Fancl, Fancm, Fancn, Fancp, Fanca/c, Wrn, Blm, Atm, and Atr. Ten of these papers present data consistent with haploinsufficiency for Brca1, Brca2, Fancd2, Fancm, Fancp, Wrn, Blm, and Atm (Table 7).

Table 7.

Human disease-related DNA repair genes

Gene −/−Lethal? Heterozygous phenotype References
Wrn No [79] Heterozygous data in ES cells only. Sensitivity to 6-thioguanine, etoposide and camptothecin follows gene dosage [79]
Blm Yes [80] Heterozygous data in MEFs only. Growth of MEFs intermediate between wild-type and null mutant. SCE not different between wild-type and heterozygote [80]
Atm No [81] The number of thymocytes in heterozygotes is intermediate between wild-type and null mutant [81]
Atr Yes [83] Heterozygous Atr mice do not display phenotypes distinct from wild type; but on a Mlh null background, Atr haploinsufficiency accelerates development of tumors [82]
Fancd2 No [75] Some tumor incidence with age, but does not appear to be statistically different from age-dependent tumors in wild-type mice [75]
Fancm No [76] SCE in response to MNNG is similar between heterozygous and wild-type mice, and endpoint survival data are not statistically different; slopes of overall and tumor-free survival appear very different between wild-type and heterozygotes [76]
Fancp No, but born at sub-mendelian ratios [77] AKA: Slx4/Btbd12. Body weight effect of heterozygosity consistent with gene dosage effect. Heterozygous mice intermediate in weight between wild-type and null mutant [77]
Brca1 Yes [66, 67] Shortened lifespan; 70% tumor incidence; tumors retain wild-type allele; increased IR sensitivity [70]
MEFs only: increased radiation-induced transformation and increased apoptosis [84]
Brca2 Yes [68, 69] MEFs only, truncated exon11 mutant. Appears to be slight increase in sensitivity to UV, x-ray, and MMS. No apparent proliferation phenotype [71]

Haploinsufficiency in BRCA genes

The BRCA genes were discovered through their association with inherited breast cancer. Through interaction with Rad51 (a homologous recombination gene), the BRCA genes have been linked to DNA repair, and BRCA1- and BRCA2-deficient cells have been shown to be HR deficient [63, 64]. In human breast and ovarian cancer predisposition, it has generally been understood that loss of heterozygosity (LOH) of the wild-type allele was required for expression of the cancer phenotype. However, King et al. [65] have demonstrated that heterozygosity of either BRCA1 or BRCA2 may be sufficient to increase breast cancer risk. In mouse, biallelic disruption of both Brca1 [66, 67] and Brca2 [68, 69] is embryonic lethal. The Brca1 heterozygous mice appear normal and are fertile up to at least 10 months, but female heterozygous animals exhibit a shortened lifespan and a 70% tumor incidence [70]. Importantly these tumors did not undergo LOH. The heterozygous animals exhibited increased IR sensitivity [70]. This is highly relevant with respect to development of secondary cancers following radiation treatment for BRCA carriers treated for breast cancer. In MEFs derived from the heterozygous animals, increased radiation-induced transformation and increased apoptosis were observed.

For Brca2, no mouse model studies have been published. However in MEFs, a slight increase in sensitivity to UV, X-ray, and MMS is observed [71]. And in a human study of transformed lymphocytes from familial heterozygous carriers, a significant impact of heterozygosity is seen with respect to SCE [72], demonstrating haploinsufficiency in a relevant human model of BRCA2 allelic insufficiency.

Haploinsufficiency in Fanc genes

In the example of Fanconi anemia, the clinical features of the disorder suggested a DNA repair defect. Not all the Fanconi anemia (FANC) genes are directly associated with DNA repair, but in general the pathway plays a role in interstrand crosslink (ICL) repair and perhaps in HR through interaction with BRCA genes (reviewed in [73]). Biallelic disruption of the Fanc genes is generally tolerated, with the exception of Fancn (Palb2), which is lethal [74]. Additionally, Fancp is viable, but homozygous mutants are born at sub-Mendelian ratios. Only three of the gene-targeting papers for the Fanc genes report a phenotype for the heterozygous mutants: Fancd2, Fancm, and Fancp. Some age-dependent tumors are observed in the Fancd2 heterozygous animals, but it does not seem that incidence in the heterzygotes differs from that in the wild-type animals [75]. So, while there are some data in the heterozygotes, the case for haploinsufficiency is weak. In the Fancm model, SCE rates are similar between wild-type and heterozygous animals, but survival curves in response to MNNG are very different between the genotypes [76]. Though the endpoint survival data are not significantly different between these genotypes, there is a definite trend toward reduced survival in the heterozygous animals. Further, early on in survival the heterozygous animals appear to be protected, resulting in survival curves with very different slopes [76]. These data suggest there is a potentially important difference in the mortality rate between the genotypes, similar to what is observed in the β-pol heterozygous model. The Fancp heterozygous animals express phenotypes with respect to body weight and hydrocephalus such that each is intermediate in severity between the wild-type and homozygous genotypes [77], consistent with gene dosage response.

Haploinsufficiency in Wrn, Blm, Atm, and ATR

RecQ helicases are involved in Bloom, Werner, and Rothmund-Thomson syndromes (reviewed in [1]). A role for these genes in DNA repair was suggested by the chromosomal instability observed in these syndromes. Only the helicases responsible for Bloom and Werner (Blm and Wrn) show evidence of haploinsufficiency. In a distinct human disease, ataxia telangiectasia (AT), severe chromosomal instability and cancer predisposition are likewise observed (reviewed in [78]). While cells from AT patients exhibit signs of DNA repair deficiency, the role in DNA repair may be more indirect, as sensors of DNA damage more than effectors. Historically, however, ATM and ATR have been considered within the context of DNA repair (by virtue perhaps of radioresistant DNA synthesis) and have been included here. In addition, heterozygous mutations in human ATR (ataxia telangiectasia and Rad3-related) have been observed in tumors displaying microsatellite instability, the type of tumors observed in HNPCC (discussed above). In total, eight papers have been analyzed (1 Wrn, 2 Blm, 1 Recql4, 3 Atm, and 1 Atr). Of these, only four presented data consistent with possible haploinsufficiency for Wrn, Blm, and Atm. Often, as we saw above, the heterozygous animals were grouped with the wild type and used as control against the null mutants. With respect to viability, homozygous deletion of Wrn results in reduced embryonic survival [79]; Blm is lethal [80]; and Atm nullizygous animals are viable [81]. The case for haploinsufficiency for these genes is not particularly strong. For Blm [80] and Atm [81] the heterozygous animals exhibit some mild phenotypes intermediate between wild-type and null genotypes. But the critical phenotypes (SCE for Blm and double strand breaks for Atm) do not seem to be impacted by heterozygosity. The case for haploinsufficiency for Wrn is stronger, as ES cells from the heterozygous animals show intermediate sensitivity to 6-thioguanine, etoposide, and camptothecin [79], suggesting an increased susceptibility in heterozygous genotypes. Atr, which is embryonic lethal for the nullizygous mutants, does not display haploinsufficiency, but the heterozygotes do accelerate development of tumors on an Mlh-null background [82]. These data are consistent with a modification of penetrance, which could be more fully investigated in the heterozygous model.

Summary

This collection of data on heterozygous mutants demonstrates a clear role for haploinsufficiency in DNA damage sensitivity and genomic instability—phenotypes that can be expected to modify penetrance of exposure and/or additional genotype effects. From this analysis, 27 genes across DNA repair pathways have been identified as exhibiting some phenotype in the heterozygous animals. The association between haploinsufficiency in these genes and disease is summarized in Table 8. Haploinsufficiency in the following ten genes showed increased tumorigenesis: β-pol, Apex1, Xpc, Xpa, Msh2, Mlh1, Pms2, Msh6, Xrcc2, and Brca1. For essentially all cases of haploinsufficiency, evidence for genomic instability exists (and phenotypes consistent with increased cancer predisposition), but studies were not always carried out to investigate tumorigenesis. For the 27 genes demonstrating haploinsufficiency, 21 clearly demonstrate an impact of heterozygosity on damage sensitivity and/or genomic instability. While the impact of increased DNA damage sensitivity on cancer predisposition and aging is obvious, these phenotypes can impact many other factors impacting health. Much research is currently underway investigating the role of DNA repair capacity on drug sensitivity and chemotherapeutic response. Much of this work has implicated DNA repair as a therapeutic target, suggesting that repair capacity (i.e., haploinsufficiency in repair) should be a critical factor in determining treatment options. Perhaps one of the most useful observations made in this analysis is that the impact of allelic insufficiency may depend upon external factors, such as other genetic predispositions, exposures and/or nutritional status. There is not always an absolute effect of haploinsufficiency, not even within the same gene. Rather, allelic insufficiency is able to modify the penetrance of other predisposing factors.

Table 8.

Disease phenotypes in DNA repair haploinsufficient mouse models

Pathway Gene Cancer (specified by type) Aging (accelerated) Other disease Modifier of penetrance
BER β-pol Lymphoma, adenocarcinoma [15] X [15]
Apex1 Lymphoma, adenocarcinoma [17] Modifies XPC-dependent UV-induced skin cancer [20]
Aag Retinal degeneration [23]
NER Xpc UVB-induced skin cancer [33] Modifies p53-dependent UV-induced skin cancer [33]
Xpa DMBA-induced papillomas [35]
MMR Msh2 Modifies tumorigenesis in APCmin model [42]
Mlh1 Gastrointestinal and non-gastrointestinal tumors [44] X [44]
Pms2 Modifies tumorigenesis in APCmin model [46]
Msh6 Carcinoma, lymphoma [47]
HR Rad21 Gastrointestinal sensitivity following irradiation [51]
Xrcc2 Increases tumorigenesis in response to IR; decreases tumroigenesis in APCmin spontantous tumorigenesis [53]
DR mAlkb1 Exancephaly [60]
BRCA Brca1 Ovarian tumors [70] X [70]
FANC Fancm X [76]
Fancp Hydrocephalus [77]

BER base excision repair, NER nucleotide excision repair, MMR mismatch repair, HR homologous recombination, DR direct reversal

A check mark is used to indicate whether there is any phenotype of accelerated aging

– indicates that no phenotype has been reported in the heterozygous mouse model. Modifier of penetrance is only marked here if a disease is associated with the haploinsufficiency

Acknowldgements

This work is supported by a grant from the Ellison Medical Foundation [DCC].

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