XPF–ERCC1: Linchpin of DNA crosslink repair

Abstract

A spectacularly toxic form of damage, the interstrand crosslink (ICL), arises when two strands of duplex DNA become covalently linked [1]. The cellular response to ICLs is of great interest because several antitumour drugs, including platinum agents and mitomycin C, kill cancer cells by inducing ICLs [2, 3]. More recently it has become apparent that metabolites continually burden cells with ICLs, which must be removed for cells to maintain function and viability. The importance of efficient ICL repair in development and health is illustrated by the clinical features of a devastating inherited syndrome, Fanconi anemia (FA), which is thought to be the result of defective ICL repair [4]. FA patients suffer from bone marrow failure, leukaemia, and solid malignancies. While the endogenous DNA-crosslinking agent, or agents, responsible for the damage that lies unrepaired in the cells of FA patients are unknown, suspects include the common metabolites formaldehyde and acetaldehyde (including that derived from ingested alcohol) and oxidised lipid species [5-7]. The machinery available to repair ICLs has expanded markedly through evolution. Both Escherichia coli and yeasts almost exclusively rely on a modified form of nucleotide excision repair (NER) [1, 8], a cut-and-paste pathway that is best known for its ability to remove UVlight-induced DNA photodimers (whose defects result in another human syndrome, Xeroderma pigmentosum [XP]). The details of how modified NER removes ICLs remain obscure and merit further investigation. Metazoans, meanwhile, have developed additional pathways for ICL repair-most significantly, an 'FA pathway' [4]. The functional characterization of genes and factors defective in FA patients (22 genes to date) have revealed a repair pathway that operates during DNA replication and possibly elsewhere in the cell cycle (although this aspect has yet to be explored systematically). Although how the FA pathway coordinates ICL repair is still subject to intense study, it appears to orchestrate initial responses to ICLs, some steps of the nucleolytic processing of ICLs, and the subsequent resolution of the incised intermediates through the sequential action of translesion-synthesis polymerases and homologous recombination reactions [9]. For mammalian cells, it is not clear whether there is a genetic or functional relationship between the NER and FA pathways in response to ICLs. Here, Mulderrig and Garaycoechea show that while both the FA and NER pathways both play important roles in response to ICLs, additional pathways also contribute to their repair [10]. At the heart of this uncertainty about the contributions of the FA and NER pathways to ICL repair is a dimeric endonuclease, XPF-ERCC1, required for both pathways and mutated in both FA (complementation group Q, FANCQ) and XP (complementation group F) [11, 12]. XPF-ERCC1 has received much attention, since it was realised several decades ago that XPF-ERCC1-deficient mammalian cells are exquisitely sensitive to ICL-inducing agents [13, 14], showing a sensit...

Dictyostelium discoideum as a Model to Assess Genome Stability Through DNA Repair

“…As well as exogenous crosslinking agents, endogenous sources of ICLs include naturally generated metabolites such as formaldehyde (Langevin et al, 2011;Nakamura and Nakamura, 2020). Vertebrates express a number of pathways to repair ICLs, including those involving the translesion DNA polymerases REV1 and REV3, and nucleases such as XPF (McHugh, 2020). The importance of ICL repair is illustrated by the developmental and health consequences of mutations in the Fanconi Anemia (FA) pathway (Duxin and Walter, 2015).…”

SUMOylation of yeast Pso2 enhances its translocation and accumulation in the mitochondria and suppresses methyl methanesulfonate‐induced mitochondrial DNA damage

“…If left unrepaired, they threaten genome integrity, cause double‐strand breaks, and impair essential cellular processes, including DNA replication, transcription and homologous recombination (HR), leading to organelle dysfunction and cell death (Baddock et al, 2020; Noll et al, 2006; Semlow & Walter, 2021). For example, reconstitution studies using cell‐free extracts or purified proteins suggest that Fanconi anemia, the most common form of hereditary bone marrow failure disorder, arises from aberrant expression and/or activity of proteins/enzymes that are involved in the ICL repair pathway (McHugh, 2020; Semlow & Walter, 2021). Several studies have also documented that almost all organisms, from bacteria to mammals, have the ability to sense and repair DNA damage caused by ICL‐forming agents by leveraging multiple DNA repair pathways, including nucleotide excision repair (NER), mismatch repair, HR and translesion DNA synthesis (Ceccaldi et al, 2016; Dronkert & Kanaar, 2001; Housh et al, 2021; Semlow & Walter, 2021).…”

Association between TOP2A, RRM1, HER2, ERCC1 expression and response to chemotherapy in patients with non-muscle invasive bladder cancer

“…High TOP2A expression patients had poorer cancer-specific, progression-free and recurrence-free survival [ 9 ]. Ribonucleotide reductase large subunit M1 (RRM1) is a rate-limiting enzyme that catalyzes the conversion of ribonucleotide to dNTPs, contributes to DNA repair, and cell growth because of the role in de novo DNA synthesis during cell replication [ 10 ]. RRM1 is an important molecular target of gemcitabine because it can control the specificity of a substrate and the activity of an enzyme.…”

“…Excision repair cross complement group 1 (ERCC1) identifies and resects the damaged DNA strand that may be representative for the crucial DNA damage repair ability of the cell. It is an important factor involved in nucleotide excision repair [ 10 ]. Reynolds et al.…”