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Published in final edited form as: Trends Genet. 2011 Oct 23;28(1):7–13. doi: 10.1016/j.tig.2011.09.003

Fanconi anemia and Bloom's syndrome crosstalk through FANCJ-BLM helicase interaction

Avvaru N Suhasini 1, Robert M Brosh Jr 1,*
PMCID: PMC3249464  NIHMSID: NIHMS326486  PMID: 22024395

Abstract

Fanconi anemia (FA) and Bloom's syndrome (BS) are rare hereditary chromosomal instability disorders. FA displays bone marrow failure, acute myeloid leukemia, and head and neck cancers, whereas BS is characterized by growth retardation, immunodeficiency, and a wide spectrum of cancers. The BLM gene mutated in BS encodes a DNA helicase that functions in a protein complex to suppress sister chromatid exchange. Of the fifteen FA genetic complementation groups implicated in interstrand cross-link repair, FANCJ encodes a DNA helicase involved in recombinational repair and replication stress response. Based on evidence that BLM and FANCJ interact, we put forward that crosstalk between BLM and FA pathways is more complex than previously thought. We propose testable models for how FANCJ and BLM coordinate to help cells deal with stalled replication forks or double strand breaks. Understanding how BLM and FANCJ cooperate will help to elucidate an important pathway to maintain genomic stability.

Chromosomal instability disorders Fanconi anemia and Bloom's syndrome

A growing number of chromosomal instability disorders are linked to mutations in helicase genes that encode DNA unwinding enzymes implicated in cellular DNA replication, repair and recombination. Given that certain helicase diseases share similar mutant cellular phenotypes, it is probable that these helicases have common or partially overlapping functions to preserve genomic stability. We will focus on this hypothesis, placing particular emphasis on the crosstalk between FANCJ and BLM helicases mutated in Fanconi anemia (FA) and Bloom's syndrome (BS), respectively.

FA [1] and BS [2] are characterized by growth retardation, reduced fertility, chromosomal instability, and predisposition to cancer. Distinguishing features of FA patients include congenital abnormalities, progressive bone marrow failure, acute myeloid leukemia, and head and neck cancers. BS patients display sunlight sensitivity, immunodeficiency, and a broad spectrum of cancers that appear early in life. Mutation of the BLM gene which encodes a DNA helicase is responsible for BS [3], and recent work using a mouse embryonic stem cell model supports a model that BLM plays early and late roles in homologous recombinational (HR) repair of double strand breaks (DSBs) [4]. The BLM-Topoisomerase IIIalpha (TopoIIIα) protein complex (Table 1) can perform double Holliday junction (HJ) dissolution [5]. BLM is also implicated in DSB resection with other factors [6].

Table 1.

Functions of FA and BLM-TopoIIIα proteins

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FA mutant cells are highly sensitive to interstrand cross-linking (ICL) agents [7], and display elevated cross-linker induced sister chromatid exchange (SCE) [8]. Of the fifteen FA genes/candidate genes currently identified [9] (Table 1), two (FANCM, FANCJ) encode DNA-dependent ATPases. FANCM regulates replication fork progression [10,11] and is thought to remodel stalled replication forks through its ATP-dependent branch migration activity [12-15]. FANCM and members of the FA core complex are required for efficient FANCD2/I mono-ubiquitination, a key activation step required for replication-coupled ICL repair [16].

FANCJ (BACH1) helicase was originally discovered by its interaction with BRCA1, a tumor suppressor molecule implicated in DSB repair [17]. FANCJ-deficient cells have a defect in DSB-induced HR and show delayed resolution of DSBs following ionizing radiation [18]. FANCJ and certain other HR proteins function downstream of FANCD2/I mono-ubiquitination in ICL repair; however, their functions in ICL repair remain to be fully characterized.

BS cells exhibit elevated SCE [2]. Although not as dramatic as BS, increased SCE has been detected in chicken knockout cell lines (FANCC [19,20], BRIP1 (FANCJ) [21], and FANCM [22]), and human cells deficient for FANCJ [23] or FANCM [24]. Human FANCJ depletion resulted in elevated mitomycin C (MMC)-induced chromosomal abnormalities, including radial structures [18,21], similar to those observed in BS [25]. Like FA, BS cells are sensitive to compounds that induce ICLs [26]. The FA pathway and BLM collaborate during S-phase to prevent and during mitosis to resolve sister chromatid bridging at fragile sites that potentially leads to micronuclei and aneuploidy [27,28].

FA core complex and BLM directly interact to preserve genomic stability [29]. FANCM was shown to serve as a bridge connecting the FA core and BLM- TopoIIIα complex [24]. The FANCJ-BLM interaction is important for BLM stability and a normal response to the replication inhibitor hydroxyurea (HU) [23], leading us to propose that cross-talk between BLM and FA pathways is even more sophisticated than previously thought. Here, we define how FANCJ and BLM helicases cooperate with each other, and propose testable models for how they collaborate to restart a stalled replication fork or facilitate DSB strand resection. Future research should address how FANCJ regulates BLM protein stability and function, and understanding molecular and cellular defects of clinically relevant helicase mutations.

FA-BLM protein complexes

BLM was first identified in a BRCA1 genome surveillance complex (BASC) with other DNA repair proteins (MSH2, MSH6, MLH1, replication protein A (RPA), ataxia telangiectasia mutated (ATM), MRE11-RAD50-NBS1 (MRN)) [30]. BLM was also found to exist in a protein complex (BRAFT) that contained the FA core complex, RPA, and TopoIIIα [29]. FANCM was shown to serve as an anchor protein to dock BLM-TopoIIIα and FA core complexes at a DNA cross-link [24]. FANCM interaction with the FA core and BLM-TopoIIIα complexes is required for SCE suppression and resistance to ICL agents, respectively.

Multiple BLM protein sub-complexes exist which may be regulated by cell cycle stage or cellular environment (e.g., replicative stress). The BLM-FANCJ interaction was enriched two-fold after cellular exposure to HU or MMC [23]. Moreover, BLM and FANCJ foci partially co-localized in HU-treated cells. BLM and FANCD2 also co-localize in MMC- and HU-induced foci and co-immunoprecipitate together [26]. A biochemical interaction between FANCD2, which binds DNA [31,32], and BLM (or FANCJ) has not been reported; however, an intact FA pathway necessary for FANCD2 mono-ubiquitination is required for BLM association with anaphase bridges [28].

BLM [33] and FANCJ [34] interact with RPA. Demonstration that FANCJ interacts with topoisomerase IIβ-binding protein 1 (TopBP1) to facilitate RPA loading onto chromatin and replication checkpoint activation [35] suggests FANCJ participates with BLM in checkpoint signaling. Interaction of FANCJ with mismatch repair complex MutLα is also required for a normal ICL-induced response [36]. It will be timely to determine if BLM (and FANCD2) play a role in the MutLα or TopBP1 signaling pathways with FANCJ.

What are the biologically relevant situations and DNA substrates that engage BLM and its protein partner FANCJ?

BLM and FANCJ helicases together synergistically unwind a DNA substrate with discontinuity in the sugar phosphate backbone in the FANCJ translocating strand [23]. The BLM-FANCJ physical association may enable the dual helicase motor to act more processively in its unwinding function, particularly on damaged DNA or specific DNA structures. Coordinate action of a 3′ to 5′ DNA helicase (BLM) with a 5′ to 3′ helicase (FANCJ) or possibly DNA translocase (FANCM) would provide a unique mechanism for unwinding or branch-migrating structured nucleic acids. It is not unprecedented that dual helicase motors operate in a synchronized manner [37]. We will discuss potentially relevant biological situations that invoke collaboration between FANCJ and BLM.

Replication stress

Perturbation of normal replication fork progression poses a source of genomic instability. FANCJ-deficient (EUFA30-F) cells like BS (PSNG13) cells are HU-sensitive [23]. Expression of a BLM-interacting FANCJ fragment exerted a dominant negative effect on HU resistance by interfering with the FANCJ-BLM association, suggesting that communication between BLM and FANCJ helps cells deal with stalled forks.

To help cells cope with replication stress, BLM helicase can regress stalled replication forks to allow repair of the replication blocking lesion [38,39]. During fork regression, newly synthesized leading and lagging strands are unwound and annealed to one another to form a chicken-foot HJ-type structure. The regressed fork can then be metabolized by non-recombinogenic or recombinogenic pathways to enable fork resumption. We propose that FANCJ may assist BLM in fork regression to enable base-pairing between unwound strands (Fig. 1A). Alternatively (or in addition), FANCJ and BLM may together branch-migrate the regressed fork structure forward again so replication may resume. This would allow replication to restart in a non-recombinogenic manner, and prevent crossovers.

Figure 1. Potential roles of BLM and its interacting partner FANCJ at stalled replication forks or double strand breaks.

Figure 1

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(a) Lesion on the leading strand template stalls replication (i). BLM/FANCJ recruitment (ii) and fork regression facilitates template switching so that leading strand can be extended past the site of the lesion to create a chicken foot junction structure (iii). BLM/FANCJ-mediated reversal of regressed fork permits restart of replication fork (iv). In the absence of junction cutting, replication would restart without SCEs. Black lines represent parental DNA strands and blue lines nascent DNA strands. (b) MRN complex senses DSB (i) and initiates end resection along with CtIP (ii). A BLM protein complex that either operates in the DNA2 pathway (BLM-DNA2-RPA-MRN) or the EXO1 pathway (EXO1-BLM-RPA-MRN) assembles at the DNA end (iii), and performs long 5′ resection by DNA2 endonuclease or EXO1 exonuclease, respectively (iv). FANCJ may putatively function in long strand resection by interacting with BLM in either of the resection complexes.

If the reversed fork HJ-like structure is cleaved by a structure-specific nuclease (e.g., MUS81) to generate a DSB, then HR is elicited to repair the broken fork. BLM interacts with MUS81 and stimulates its endonuclease activity [40]; therefore, it may be that FANCJ also interacts with MUS81 or other structure-specific nucleases to help repair forks. SLX4, a docking protein for the structure-specific nucleases MUS81-EME1, XPF-ERCC1, and SLX1, is also involved in cross-link repair in a manner dependent on FANCD2 monoubiquitination [41]. Defective HJ resolution leads to aberrant chromosome morphology in human cells [42], which may be suppressed by coordinate action of BLM and FANCJ. Careful study of FA protein interactions should begin to elucidate mechanics of ICL repair and response to stalled forks.

Double strand break repair

In replicating cells, the highly toxic DSBs can be repaired by HR. A key intermediate in HR is the three-stranded D-loop that arises by RAD51-mediated invasion of a single-stranded DNA molecule into recipient duplex. BLM [43] or FANCJ [44] may act to disrupt the D-loop to inhibit inadvertent HR or regulate the process at an early stage between homeologous sequences. D-loop disruption by FANCJ or BLM may also be relevant to synthesis-dependent strand annealing (SDSA) which follows a cycle of DNA duplex unwinding and strand annealing events to enable DSB repair. Genetic evidence has implicated Drosophila melanogaster BLM in SDSA [45], suggesting that mammalian BLM is also an active player. However, it is unclear if FANCJ coordinates with BLM during SDSA.

BLM is implicated in an early stage of DSB repair in which strand resection from a DNA end occurs to provide a 3′ single-stranded DNA tail for strand invasion [6,46,47]. Strand resection appears to be a complex process involving distinct constellations of helicases, nucleases, DNA binding proteins, and accessory factors. Concerted action of FANCJ with BLM at an early step of DSB processing would be consistent with evidence that FANCJ helicase participates in DSB repair [17,18]. We predict that strand resection is facilitated by FANCJ and BLM helicases translocating on opposite strands of the broken double-stranded DNA end to promote access to structure-specific nucleases (EXO-1, DNA2) (Fig. 1B). The FANCJ-BLM partnership may facilitate resection at chemically modified blocked DNA ends or through G-rich sequences prone to form G-quadruplex (G4) structures (next section). Careful examination of helicase and nuclease recruitment kinetics to localized damage in living cells should provide insight. Moreover, mammalian genetic systems should further help to decipher the mechanisms of DSB and ICL repair.

G-quadruplex DNA metabolism

G4 DNA consisting of stacked planar quartets composed of four guanines that interact by Hoogsteen hydrogen bonding can be formed by G-rich sequences widely distributed throughout the genome [48]. G4 structures potentially impede cellular DNA replication or transcription. Both FANCJ [49,50] and BLM [51] were shown to efficiently unwind G4 DNA substrates, but require single-stranded tails of opposite polarities. A FA-J patient cell line (EUFA0030) was found to accumulate large genomic deletions in the locality of G4-forming sequences [49]. It remains to be seen if BLM-deficient cells also display genomic instability at regions characterized by the G4 DNA signature.

FANCJ and BLM helicases may collaboratively act upon G-quadruplexes found in specific chromosomal regions under certain cellular (environmental) or genetic conditions. Specialized function of BLM and FANCJ at telomeres is supported by the observation that they were found to be specifically bound to telomeric DNA in telomerase negative cells engaged in alternative lengthening of telomeres (ALT) maintenance pathway [52]. BLM is required for suppression of telomere fragility [53], and FANCJ-deficient cells, but not FA-A nor FA-D2 cell lines, are hypersensitive to the G4-binding ligand telomestatin (TMS) [50], a compound that induces telomere capping defects [54,55]. The 3′ to 5′ BLM directionality seems better suited to enable a polymerase catalyze DNA synthesis through a G-rich sequence and avoid collision with replication machinery. However, biochemical results suggest that a G4 structure at the very 3′ telomeric end would be resistant to BLM helicase and require other resolving mechanisms [56].

G-quadruplexes assume a number of different conformations in which one or multiple strands can be aligned in parallel or anti-parallel fashion with intervening loops [57]. FANCJ and BLM may act upon intramolecular G-quadruplexes formed by human telomeric repeats in coordinate fashion to prevent capping defects. Depending on G-tetrad number and exposure of adjacent single-stranded regions, FANCJ and BLM may initiate unwinding from internal or proximal regions of telomeric sequences, or intervening loops. Given evidence that translesion synthesis DNA polymerases eta and kappa are required for maintenance of guanine-rich DNA in vivo [58], future studies should determine if FANCJ/BLM facilitate translesion polymerase replication through G-rich elements. A relationship between FANCJ and polymerase eta has already been established, whereby FANCJ uncoupled from BRCA1 promotes polymerase eta-dependent bypass for cellular resistance to DNA cross-linking agents or ultraviolet light [59].

BLM protein stability is strongly dependent on FANCJ

BLM is degraded by a proteasome-mediated pathway in FANCJ-deficient cells in a specific manner since levels of BLM-interacting proteins (RPA, TopoIIIα, FEN-1) were not affected [23]. Physical interaction between BLM and FANCJ helps to stabilize BLM protein in vivo; however, the converse is not true, i.e., FANCJ level remained the same in BLM mutant and corrected cells. BLM levels are known to be affected when certain interacting partners (e.g., RMI1 [60] and RMI2 [61]) are deficient, suggesting that BLM folding or susceptibility to proteasome degradation is highly influenced by interacting/associated proteins in FA or related pathways.

BLM sumoylation, DNA repair, and a potential FA connection

Demonstration that BLM is susceptible to proteasome-mediated degradation when its protein partner FANCJ is absent suggests involvement of post-translational modification(s) in BLM protein stability. BLM is modified in vivo by the small ubiquitin-related modifiers (SUMOs) SUMO-2 and SUMO-3 [62]. This may be relevant to BLM stability since sumoylated residues can be bound by ubiquitin ligases that target proteins for ubiquitylation, which can lead to protein degradation through a proteasome pathway [63].

BLM sumoylation was already shown to have important biological consequences. BLM SUMO mutants failed to localize to promyelocytic bodies where BLM is thought to enact its DNA repair functions, and the cells accumulate more spontaneous [64] or HU-induced [65] γH2AX foci than controls, attesting to the importance of BLM sumoylation for DNA damage accumulation. One would expect that replication fork damage would induce HR; however, this is not the case in SUMO-mutant BLM cells [65]. Moreover, RAD51 poorly localizes to damaged forks in SUMO-mutant BLM cells, which probably contributes to HR deficiency and DSB accumulation after replication stalling. Consistent with these data, sumoylated recombinant BLM binds RAD51 more efficiently than unsumoylated protein.

These observations raise the question if BLM sumoylation plays a role in the fate of BLM stability. If the absence of FANCJ unmasks a SUMO site in BLM that is recognized by a ubiquitin ligase, then BLM may become destined for proteasome-mediated degradation. It was proposed that BLM sumoylation could promote HR-repair of broken replication forks through recruitment or retention of RAD51 at damaged forks [65]; however, in the absence of FANCJ, this critical role of BLM may be abolished since the helicase is degraded and/or the helicases fail to coordinately interact.

Future work should address the underlying mechanism whereby FANCJ controls BLM stability and if they collaborate to repair broken replication forks in a RAD51-dependent manner. Signaling through a checkpoint kinase may affect BLM degradation when FANCJ is deficient. This was observed for FANCM in which Chk1 prevents FANCM from being degraded by the proteasome after DNA damage [10]. The FA network is one in which protein partnerships exist to maintain stability of interacting proteins as well as coordinate functions to enact DNA repair processes. For example, MRN regulates FANCD2 stability and function during DSB repair [32].

FANCJ clinical mutations and disease phenotypes

FA clinical symptoms may be partly attributable to the nature of the mutation. For example, a patient derived FANCJ-A349P mutation in the iron-sulfur domain uncoupled ATPase and translocase activity from helicase activity or disruption of protein-DNA complexes [66]. Furthermore, FANCJ-A349P expressed in normal cells impaired their resistance to DNA cross-linking agents or TMS. Clinical significance of the FANCJ-A349P allele or other helicase-inactivating mutations in heterozygote carriers remains to be determined. Given evidence from cell-based models that dysfunctional helicase proteins exert a spectrum of dominant negative effects [67], future studies should directly evaluate genotype-phenotype relationships.

In some instances, a FANCJ mutation may exert an effect on stability of BLM or other protein partners. Full-length FANCJ protein was absent in certain FA-J patient cell lines, but residual full-length FANCJ protein was detected in a cell line (EUFA776) harboring a FANCJ missense mutation [68]. Reduced FANCJ expression was reported for several breast cancer associated FANCJ mutants [69]. Decreased BLM protein associated with FANCJ deficiency may contribute to the nature and degree of chromosomal instability and associated phenotypes observed in FA-J patients or possibly individuals with a FANCJ mutation predisposing them to breast cancer. Individuals with FANCJ haploinsufficiency may display compromised DNA repair capacity due to reduced BLM. This hypothesis should be readily testable, and may also be relevant to cross-talk between FANCD2 and MRN. Future studies of patient derived mutations will be informative for understanding the molecular basis of disease.

Concluding remarks and future perspectives

Future research should address if FANCJ-BLM coordination is required for efficient restart of a stalled replication fork or DSB repair. Elaborate mechanisms that help cells deal with diverse forms of replication stress are likely to require catalytic action of FANCJ and BLM helicases to enable smooth progression or fork restart. The next challenge is to define if specialized regions of the genome, such as telomeres or fragile sites, are targeted by the helicase partnership. Chromatin immunoprecipitation studies using cells exposed to agents that induce replication fork stalling may help to identify sequences enriched for interaction with both FANCJ and BLM.

In terms of DSB repair, a useful approach would be to reconstitute DNA end resection with FANCJ and its interacting proteins (BLM, BRCA1, RPA, and MRN (our unpublished data)) along with structure-specific nucleases (DNA2, EXO-1). These efforts will be significantly enhanced if chromatinized templates are used to better reflect the in vivo situation. Cell-based studies with defined substrates should provide a better understanding of FANCJ's role in DNA end resection and how its interaction with BLM is important. Genetic and cell biological experiments will be required to confirm and extend observations from biochemical studies.

The helicase interaction network is becoming increasingly more complex. Characterization of how BLM/FANCJ post-translational modifications regulate their interaction is therefore a high priority. FANCJ phosphorylation state was already shown to regulate its interaction with BRCA1 [70]. Additional post-translational modifications of FANCJ or BLM, such as sumoylation, are likely to be important in the regulation of pathway function.

There is still much to learn about the FA pathway and how it coordinates with other proteins to maintain genomic stability. Predisposition to cancer in BS and FA, as well as the connection of BRCA-associated FA proteins with breast cancer, suggest that BLM and FANCJ are indeed genome caretakers with tumor suppressor functions. A systematic investigation of patient mutations and FANCJ-BLM interactions should yield new insights that will hopefully have translational applicability.

Acknowledgements

This work was supported by the Intramural Research program of the National Institutes of Health, National Institute on Aging, and the Fanconi Anemia Research Fund (RMB).

Glossary

Anaphase bridges

a continuous string of chromatin stretching from one anaphase pole to the other. Anaphase bridges can generate micro-nuclei and lagging chromatin as a consequence of bridge rupture by the force of the mitotic spindle or during cytokinesis. Increased number of anaphase bridges and micro-nuclei are seen in Bloom's syndrome cells

Chicken foot

a four-stranded Holliday junction-like structure that is generated by annealing of leading and lagging strands and resumption of leading strand synthesis using the lagging strand as template

D-loop

a DNA structure (displacement loop) in which two strands of a double-stranded DNA molecule are separated for a stretch and held together by a third strand which contains base sequence that is complementary to one of the main strands with which it is paired

Helicase

an enzyme that catalytically unwinds structured nucleic acids by disrupting complementary hydrogen bonds in a reaction driven by the hydrolysis of nucleoside triphosphate

Holliday junction (HJ)

mobile junction between four strands of DNA that represents an intermediate in genetic recombination and important for genomic stability

Hydroxyurea (HU)

an antineoplastic drug compound that reduces production of deoxyribonucleotides by inhibiting the enzyme ribonucleotide reductase. Cellular exposure to HU induces replication stress

Interstrand cross-link (ICL)

a covalent linkage between complementary strands of a DNA double helix. DNA replication is blocked by cross-links, which cause replication arrest and cell death if the cross-link is not repaired

Mitomycin C (MMC)

a naturally occurring compound used as a chemotherapeutic agent that covalently introduces DNA cross-links. MMC is used in diagnostic tests for Fanconi Anemia since cells from these patients have genetic defects in DNA cross-link repair

Strand resection

process whereby a 5′ end of a double strand break is trimmed back to create a 3′ single strand overhang. Production of a 3′ single-strand overhang permits homologous recombinational repair of the double strand break

Synthesis dependent strand annealing (SDSA)

a mechanism of double strand break repair during mitosis that allows for error-free repair of the break without exchange of adjacent sequences

Footnotes

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