DNA–protein crosslink repair

Abstract

DNA-protein crosslinks (DPCs) are highly toxic DNA adducts, but whether dedicated DPC-repair mechanisms exist was until recently unknown. This has changed with discoveries made in yeast and Xenopus laevis that revealed a protease-based DNA-repair pathway specific for DPCs. Importantly, mutations in the gene encoding the putative human homologue of a yeast DPC protease cause a human premature ageing and cancer predisposition syndrome. Thus, DPC repair is a previously overlooked genome-maintenance mechanism that may be essential for tumour suppression.

Functional Toxicogenomic Profiling Expands Insight into Modulators of Formaldehyde Toxicity in Yeast

“…DPCs can be repaired by various mechanisms; if the lesion cannot be removed by NER or base excision repair (BER), the replication fork may arrest at the site of damage, eliciting HR and/or damage tolerance systems such as PRR/TLS to help restart the stalled replication fork (Grogan and Jinks-Robertson, 2012; Stingele and Jentsch, 2015). Nakano et al (2007) demonstrated that in bacteria, NER repairs DPCs with small crosslinked proteins, whereas RecBCD-dependent HR processes oversized DPCs.…”

“…The same group found HR, not NER, is the major contributor to DPC tolerance in mammalian cells, while also showing DPCs accumulate in HR-deficient cells–suggesting fork breakage at DPCs initiates HR to reactivate stalled forks (Nakano et al, 2009). The Fanconi anemia pathway may mediate HR repair of DPCs in higher eukaryotes (Stingele and Jentsch, 2015); Ren et al (2013) has illustrated human lymphoblasts deficient in FANCD2 , a homologous repair gene involved in DNA crosslink repair via the Fanconi anemia pathway, were more susceptible to FA, with DPCs increasing in a dose-dependent manner. While there are a lack of Fanconi anemia functional homologs in yeast, our studies confirmed a requirement for RAD5, RAD18 , and RAD51 , genes identified as factors in the Fanconi-like crosslink pathway in yeast (Daee and Myung, 2012), in FA tolerance—suggesting HR repair may be mediated by the Fanconi-like pathway in response to FA in yeast.…”

Formation and repair of DNA-protein crosslink damage

“…Each gray of ionizing radiation is thought to produce about 150 DPCs in the genome per cell [Barker et al, 2005]. Several cancer drugs induce DPCs, including nitrogen mustards, 5-aza-2′-deoxycitidine (5-azadC, also clinically known as decitabine), and platinum-based agents such as cisplatin- and transplatin-derivatives [Santi et al, 1983; Barker et al, 2005; Loeber et al, 2009; Ide et al, 2011; Stingele and Jentsch, 2015]. The chemotherapeutic drugs camptothecin and etoposide are used clinically to induce a specialized class of DPCs, as will be discussed later.…”

“…Failure to repair DPCs leads to a variety of genotoxic consequences, such as chromatid breaks, chromosomal aberrations, and mutations [Stingele and Jentsch, 2015]. It has been observed several decades ago that acetaldehyde exposure increases the incidence of mutations, sister chromatid exchanges, micronuclei, and aneuploidy in mammalian cells [Dellarco, 1988].…”

Timeless insights into prevention of acetaldehyde genotoxicity?

“…These proteases are homologous to the human DVC1-Spartan protease. 7 Interestingly, germline mutations in the DVC1-Spartan gene in humans results in premature aging and an increased risk of liver cancer. 7 A summary of the main pathways for protecting against acetaldehyde genotoxicity identified by Noguchi et al 4 is given in Fig.…”