ReviewCrosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance
Introduction
DNA repair mechanisms play a critical role in maintenance of genomic integrity as damage caused by spontaneous mutations, radiation or chemotherapeutic drugs if not accurately repaired can lead to genomic instability. Depending upon the type and location of the lesion, processes handling DNA damage can be classified into four broad classes: nucleotide excision repair (NER), homologous recombination repair (HRR), nonhomologous end joining (NHEJ), and translesion synthesis (TLS) or postreplication repair (PRR). Whereas the former three pathways represent true repair mechanisms, the TLS or PRR pathway enables DNA repair by allowing lesions or structural aberrations blocking replicative DNA polymerases to be tolerated. The repair pathways are highly conserved and are recruited to repair modified nucleotides, DNA strand breaks, or both. The specificity and fidelity of these processes vary but may be mutually compensatory in certain contexts [1].
DNA damaging agents used in cancer therapy induce a variety of toxic DNA lesions. Among these, agents such as bifunctional alkylating drugs, platinum compounds, and psoralen introduce both intrastrand crosslinks (the crosslinking of two bases on the same DNA strand) and interstrand crosslinks or ICLs (the crosslinking of two bases on opposite strands of DNA). Mitomycin C mainly induces ICLs [2], whereas psoralen induces up to 40% ICLs [3]. In contrast, 90% of the crosslinks induced by cisplatin are intrastrand crosslinks and 5–8% are ICLs [3], [4], [5], [6]. Doxorubicin, another commonly used chemotherapeutic drug, is a DNA intercalator which prevents topoisomerase from binding DNA and blocks DNA religation at low concentration [7]. In addition, doxorubicin forms covalent adducts that exhibit characteristics of ICLs [8]. Most ICLs produce major distortions to DNA structure, which prevent DNA strand separation. Thus ICLs are particularly deleterious as they block DNA replication and/or DNA transcription, and if unrepaired they can lead to single strand breaks (SSBs), double strand breaks (DSBs), and chromosomal rearrangements [9]. Therefore processes that allow cancer cells to survive in the face of these damaging lesions, such as upregulation of DNA damage response (DDR) and DNA damage tolerance (DDT) pathways are advantageous to cancer cells [10]. It is no surprise then that many cancer cells exhibiting chemoresistance demonstrate upregulated DDR and DDT pathways. TLS, a component of the DDT pathway, constitutes a critical initial step in ICL repair as it prepares the leading template strand for repair by HR pathway. The HRR pathway is essential for stabilization and restart of stalled DNA replication forks. Stalled replication forks activate the Fanconi anemia (FA) pathway which cooperates in a common biochemical FA/BRCA HRR pathway to detect and repair stalled replication forks [11], [12]. In this review, we will discuss the TLS pathway in relation to the FA network and HRR pathway, the contribution of their crosstalk in ICL repair and acquisition of chemoresistance, and the potential value of targeting the TLS pathway to restore chemosensitivity.
Section snippets
Translesion synthesis pathway
Most DNA damage is successfully removed or repaired by error-free DNA repair pathways. However, if the DNA lesions are not repaired before replication because of inefficient repair mechanisms or checkpoint controls, the damaged DNA cannot be utilized as a template for replication by high fidelity DNA polymerases as it results in replication fork stalling and replication gaps. To enable completion of DNA replication and cell survival, cells utilize error-free or error-prone lesion bypass
The Fanconi anemia network
Fanconi anemia (FA) is a rare autosomal recessive genetic disease caused by mutations in the Fanconi anemia protein cluster. 14 FANC genes have been identified including FANCA, FANCB, FANC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (BACH1; BRIP1), FANCL, FANCM, FANCN (PALB2) and FANCP (SLX4). Mutations in RAD51C, a RAD51 paralog, have also been identified in FA patients. Fanconi anemia is characterized by hypersensitivity to DNA ICL agents, chromosomal instability, and
Homologous recombination repair
In response to double strand breaks (DSBs), cells utilize the HRR pathway which relies on the undamaged sister chromatid as a template for repair. Due to this reliance on the sister chromatid, HRR is active during S and G2 phases of the cell cycle. Throughout the remainder of the cell cycle NHEJ is utilized, which will not be discussed here. Repair by HR requires three major steps: end resection, strand invasion, and resolution. End resection involves the activities of MRE11-RAD50-NBS1 (MRN)
PRR pathway, FA network and HRR pathway crosstalk
The PRR pathway can initiate error-prone or error-free repair depending upon the modification made to PCNA, i.e., monoubiquitination or polyubiquitination, respectively. Evidence shows that initiation of error-prone and error-free repair by the PRR pathway contributes to increased activation of the FA network and the HRR pathway, which is discussed below.
FA/BRCA/HRR/TLS crosstalk and chemoresistance
Among the various chemotherapeutic drugs used for cancer treatment, ICL-inducing agents are most widely used, particularly in treatment of solid tumors. ICL-inducing agents include nitrogen mustards, mitomycin C, platinums and psoralens. Cyclophosphamide, a nitrogen mustard alkylating agent, with trade names Endoxan, Cytoxan, Revimmune, Procytox and Neosar are routinely administered as first line treatment for leukemia, lymphoma and metastatic breast cancer [75], [76]. Cisplatin is used for
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Acknowledgements
Work in the laboratory has been supported by grants W81XWH-09-1-0608 and CA178117 from the Department of Defense and National Cancer Institute, respectively. BH was supported by an Initiative for Maximizing Student Diversity (IMSD) training grant awarded to Wayne State University.
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Compromised repair of radiation-induced DNA double-strand breaks in Fanconi anemia fibroblasts in G2
2020, DNA RepairCitation Excerpt :The activated FA core complex functions as a ubiquitin ligase to activate the paralogs FA D2 and I by monoubiquitylation to form the FA ID heterodimer (FA complex II). The FA ID heterodimer is considered as the main regulator of the FA/BRCA pathway via interaction with downstream factors of HR, NER, and TLS (FA complex III) [4]. During the ICL unhooking event introduced by the ID complex and conducted by SLX4 (FA P), the structure-specific endonuclease ERCC4/XPF (FA Q)-ERCC1 heterodimer and the crossover junction endonuclease MUS81-EME1 [5], a DNA double-strand break (DSB) is generated by nucleolytic incision.
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2020, DNA RepairCitation Excerpt :HR machinery acts at stalled replication forks to complete DNA repair. HR may also act with TLS to bypass remaining DNA lesions and start DNA replication [32–36]. ATR plays an important role in ICL repair.
Impact of genetic factors on platinum-induced gastrointestinal toxicity
2020, Mutation Research - Reviews in Mutation ResearchCitation Excerpt :Translesion DNA synthesis (TLS) can allow the completion of replication through DNA lesions by a series of low-fidelity polymerases, including the B-family DNA polymerases (a catalytic subunit, REV3 and an accessory subunit, REV7), Y-family DNA polymerases (POLh, POLk, POLi, and REV1), and PCNA [102]. TLS is a crucial initial step in ICL repair as it synthesizes DNA across the lesion thus preparing the damaged DNA template for repair by the HR pathway and FA network [103]. Three studies have explored the role of SNPs in TLS genes with platinum-induced GI toxicity including REV3 and REV7 [104], POLK [105], RAD18 (activation of TLS) [106] (Supplementary Table 8).