Review
Crosstalk between translesion synthesis, Fanconi anemia network, and homologous recombination repair pathways in interstrand DNA crosslink repair and development of chemoresistance

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Abstract

Bifunctional alkylating and platinum based drugs are chemotherapeutic agents used to treat cancer. These agents induce DNA adducts via formation of intrastrand or interstrand (ICL) DNA crosslinks, and DNA lesions of the ICL type are particularly toxic as they block DNA replication and/or DNA transcription. However, the therapeutic efficacies of these drugs are frequently limited due to the cancer cell's enhanced ability to repair and tolerate these toxic DNA lesions. This ability to tolerate and survive the DNA damage is accomplished by a set of specialized low fidelity DNA polymerases called translesion synthesis (TLS) polymerases since high fidelity DNA polymerases are unable to replicate the damaged DNA template. 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 homologous recombination (HR) pathway and Fanconi anemia (FA) network, processes critical for ICL repair. Here we review the molecular features and functional roles of TLS polymerases, discuss the collaborative interactions and cross-regulation of the TLS DNA damage tolerance pathway, the FA network and the BRCA-dependent HRR pathway, and the impact of TLS hyperactivation on development of chemoresistance. Finally, since TLS hyperactivation results from overexpression of Rad6/Rad18 ubiquitinating enzymes (fundamental components of the TLS pathway), increased PCNA ubiquitination, and/or increased recruitment of TLS polymerases, the potential benefits of selectively targeting critical components of the TLS pathway for enhancing anti-cancer therapeutic efficacy and curtailing chemotherapy-induced mutagenesis are also discussed.

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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