An introduction for the special issue on environmental health and genome integrity

Exposure to environmental agents or toxins can result in many different types of DNA lesions in the genome of cells, such as interstrand crosslinks (ICLs), DNA-protein crosslinks (DPCs), double-strand breaks (DSBs), single-strand breaks (SSBs), ultraviolet (UV)-damage, and base damages (Lindahl 1993; Yan et al. 2014). Environmental genotoxicity from these DNA damages via direct or indirect mechanisms is causally linked to diverse pathological conditions including cancer and neurodegenerative disorders (Jackson and Bartek 2009; Yan et al. 2014). In response to DNA lesions, cells have evolved several stress response pathways including DNA repair pathways, DNA damage response (DDR) pathways, and DNA damage tolerance (DDT) pathways (Friedberg 2008; Ciccia and Elledge 2010; Branzei and Psakhye 2016; Blackford and Jackson 2017; Pilzecker et al. 2019). The ways in which environmentally-induced DNA lesions are sensed, processed and repaired can critically impact cell viability, genome stability and disease susceptibility. Whereas genome integrity has been studied extensively for decades, recently and ongoing studies by numerous investigators continue to reveal surprising and important new details concerning molecular mechanisms of genome integrity, chromosome stability and human susceptibility to environmentally-induced disease. For examples, recent work expands our appreciation of the diversity of genome integrity mechanisms dedicated to sensing and signaling the presence of diverse DNA lesions. It is becoming increasingly apparent that the molecular anatomy of the genome integrity differs considerably in different biological setting and that the same genome integrity components can be deployed in different ways depending on physiological context. We are gaining new appreciation for the ways in which different branches of genome integrity interact with each other, sometimes serving redundant roles that may be revealed only in certain genetic backgrounds. Furthermore, decisions to deploy specific branches of genome integrity are subject to stringent control and pathway choice may be pathologically disrupted in ways that can have major impact on genome stability and mutational signatures. New connections are emerging between genome integrity and other pathways not typically considered to be linked to DNA repair and DDR pathways, and that these serve to integrity genome integrity with other processes during normal and pathological states.

The Special Issue (SI) titled “Environmental health and genome integrity” focuses on the relationship between environmental exposures, genome maintenance, and human health, and emphasizes new emerging themes and discoveries in the field of genome integrity. Reviews in this SI will explore ways in which our current knowledge of genome integrity pathways reveals how environmental agents affect human health. There will be a particular emphasis on how our understanding genome maintenance mechanisms can be translated to better predict, prevent and treat environmentally-induced disease in humans.

Rageul and Kim describe developments of Fanconi anemia (FA) pathway and its role in ICL repair (Rageul and Kim 2020). Due to the blockage of unwinding of DNA double strands, ICLs compromise DNA replication and transcript, leading to a great threat to genome stability. In diagnostic, therapeutic and experimental settings, ICLs are typically induced by cytotoxic chemotherapeutic drugs such as cisplatin and mitomycin C. However, sensitivity to extrinsic ICL agents does not explain the clinical features of FA patients and there has been immense interest in identifying the putative endogenous DNA lesions that are remediated by the FA pathway. Interesting recent work suggests that reactive aldehydes such as acetaldehyde and formaldehyde, which are abundant in the environment and also as common byproducts in metabolic pathways, are proposed as endogenous source of forming DNA ICLs, whose accumulation may account for bone marrow failure in FA patients. To eliminate toxic intracellular active aldehydes, alcohol dehydrogenase 5 (ADH5) and aldehyde dehydrogenase 2 (Aldh2/ALDH2) are the two critical enzymes involved in metabolism and detoxification processes (Langevin et al. 2011; Pontel et al. 2015). Thus, the review by Rageul and Kim provides an new perspective on our understanding of reactive aldehydes, bone marrow failure, and FA in the biological processing of ICLs (Rageul and Kim 2020).

Kojima and Machida review recent advances in our understanding of how DPCs are induced, sensed, and repaired (Kojima and Machida 2020). DPCs can be generated from ionizing radiation, UV radiation, and reactive aldehydes from endogenous and exogenous sources, as well as chemotherapeutic drugs (Ide et al. 2011; Duxin et al. 2014). DPCs are covalently crosslinked and trapped on DNA, leading to impairments of DNA replication and transcription machineries (Duxin et al. 2014; Nakano et al. 2017). DPCs can be resolved by nucleotide excision repair (NER) and homologous recombination (HR) repair pathways as well as replication-mediated proteolysis-based mechanism (Ide et al. 2011; Duxin et al. 2014). Kojima and Machida summarize the mechanisms of formation and repair or DPCs from environmental exposures such as formaldehyde, 1,3-butadiene, and hexavalent chromium (Kojima and Machida 2020). Mechanisms of DPC formation include direct mechanism via crosslinking proteins to DNA and indirect mechanisms through generation of radicals on DNA and proteins, abortive enzymatic reactions of topoisomerases (Top1 and Top2), and generation of AP sites (Kojima and Machida 2020). They also explain how DPC proteins are degraded by proteases such as SPRTN, the proteasome, and TDP1/TDP2, and how genome maintenance pathways such as TLS, NER, and the MRN complex cooperate to process DPC-induced damage (Kojima and Machida 2020).

Sarkar and Gaddameedhi provide a perspective on how solar UV-induced DDR transforms melanocytes to environmental melanomagenesis (Sarkar and Gaddameedhi 2020). UV exposure induces bulky DNA photolesions (e.g., cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts), which are primarily repaired by NER pathway including global genome-NER and transcription-coupled-NER sub-mechanisms (Sancar et al. 2004; Hoeijmakers 2009). NER pathway defects have long been implicated in skin cancers including melanoma and a genetic syndrome named xeroderma pigmentosum (XP) (Hoeijmakers 2009; Feltes and Bonatto 2015). In this SI, Sarkar and Gaddameedhi examine how solar UV drives melanomagenesis and emphasize how various regulators in NER and DDR pathways in melanocytes (e.g., paracrine hormones such as αMSH and ET-1 synthesized by neighboring keratinocytes) impact the carcinogenic process. Additionally, an endogenous timekeeping mechanism mediated by circadian clock proteins is also highlighted for the regulation of UV-induced DDR pathways (Sarkar and Gaddameedhi 2020).

Tomida and coauthors summarize new ways in which DNA DSB pathway choice is regulated (Fackrell et al. 2020). DSB represents one of the most toxic DNA lesions as they can result in loss of chromosome regions or chromosome translocations (Hoeijmakers 2009; Jackson and Bartek 2009). DSBs are repaired by HR, nonhomologous end joining (NHEJ), or alternative end joining (Chang et al. 2017). Cell cycle phases and critical repair factors such as 53BP1 and BRCA1 have contributed to different DSB repair pathway choices (Scully et al. 2019). In this SI, Tomida and coauthors describe work defining FAM35A as a critical new determinant of DSB repair pathway choice and discuss the impact of FAM35A on genome stability and cancer (Fackrell et al. 2020). They summarize discovery and characterization of FAM35A structure and function, and explain how FAM35A affects cellular responses to DSB-inducing agents (Fackrell et al. 2020). In addition, abnormal expression and alterations of FAM35A may suggest targeting FAM35A has a potential as a cancer biomarker (Fackrell et al. 2020).

Brieno-Enriquez, Weiss and coworkers review the function and regulation of the ATR-Chk1 DDR pathway in meiosis (Pereira et al. 2020). In somatic cells, the ATR-Chk1 DDR pathway mediates S-phase and G2/M checkpoints in response to stalled DNA replication forks or DNA damage (e.g., following exposure to environmental genotoxins such as UV radiation and Polycyclic Aromatic Hydrocarbons) (Jackson and Bartek 2009; Ciccia and Elledge 2010; Saldivar et al. 2017). Intriguingly, recent studies reveal that ATR-Chk1 DDR pathway is also activated by DSBs after the 5'-3' end resection or by SSBs after the 3'-5' end resection (Shiotani and Zou 2009; Lin et al. 2020). Interestingly however, in germ cells, components of the ATR-Chk1 DDR pathway play key roles in meiotic recombination that are distinct from their functions in mitotic cells, yet critical for genome integrity (Pereira et al. 2020). The creation of haploid gametes through the specialized process of meiosis involves an intricate series of chromosome dynamics and the intentional creation and repair of DSBs. It follows that DDR mechanisms, including many of the same pathways that respond to genotoxin-induced DNA lesions in somatic cells, are crucial during meiosis. Pereira and colleagues discuss the regulation and function of the key DDR kinase ATR during meiosis, including both its canonical activities related to DNA repair as well as meiosis-specific roles for ATR in processes such as meiotic silencing (Pereira et al. 2020). These meiotic DDR activities are essential to prevent infertility and birth defects, highlighting the central importance of genome maintenance in normal developmental processes as well as in response to exogenous stresses.

Tateishi and colleagues describe an unexpected new role for the protein kinase Chk2 in responses to DNA replication stress (Mustofa et al. 2020). ATM-Chk2-mediated DDR pathway is usually activated in response to DSBs to coordinate cell cycle progression and transcription with DNA repair (Jackson and Bartek 2009; Ciccia and Elledge 2010). Chk2 has been demonstrated as a tumor suppressor and has been targeted for anticancer therapy (Stracker et al. 2008). Tateishi et al. explain how Chk2 plays an important role in responding to DSBs that arise secondarily via DNA replication fork collapse in certain genetic backgrounds (such as TLS deficiency) (Mustofa et al. 2020). The authors explain how the different branches of the DDR pathways do not act insolation but instead interact extensively, serving back-up or redundant roles to respond dynamically to DNA damage. Often, these redundancies can be revealed through the use of different genetic backgrounds. Interestingly, the new roles for Chk2 described by Tateishi et al. may explain how Chk2 variants such as the germline frame-shifted allele Chk2*1100delC contributes to tumorigenesis in humans (Mustofa et al. 2020).

Guo and coworkers provide an update on DDT mechanisms that are employed to bypass unrepaired DNA damage (Ma et al. 2020). When DNA lesions can’t be repaired prior to DNA synthesis, cells have evolved four different modes of DDT pathway including translesion synthesis, template switching, fork reversal, and fork restart by repriming (Chang and Cimprich 2009; Pilzecker et al. 2019). Two key events in TLS pathway (i.e., polymerase switching and PCNA mono-ubiquitination) in mammalian cells are highlighted in this review (Ma et al. 2020). The distinct regulation and function of protein-protein interactions, post-translational modifications, transcription and noncoding RNAs in the TLS process provide us better understanding of regulatory mechanisms of DDT in genome integrity (Ma et al. 2020). Because TLS deficiencies have been implicated with various diseases such as cancer and neurodegenerative diseases (Pilzecker et al. 2019), our knowledge on TLS regulations will benefit for drug development that targets TLS pathway.

Finally, Li and Sancar provide a historic overview of various methods of detecting DNA damage and repair and highlight the current methodologies available for detection of environmentally induced DNA damage and repair (Li and Sancar 2020). Sensitive and accurate measurements of DNA damage and DNA repair dynamics have been extremely challenging (Hu et al. 2015). However, recent development of next generation sequencing (NGS) technologies has facilitated different genome-wide damage/repair detection technologies. Li and Sancar describe traditional methods for detecting DNA damage and repair (e.g., gel electrophoresis, radioactive labeling, as well as fluorescence labeling or staining) and also explain the NGS-based and most recent third-generation sequencing-based damage/repair detection methods (Li and Sancar 2020). Future mechanistic studies utilizing these genome-wide damage/repair detection methods will provide novel insight into how genome integrity is maintained in the response to environmental toxins and endogenous insults.

Collectively, the perspectives in this SI provide us updated understanding on genome integrity and environmental health. Our knowledge in genome integrity and environmental health will help to provide insight into better strategies on treatment of human diseases such as cancer and neurodegenerative disorders.