Mechanism and regulation of incisions during DNA interstrand cross-link repair

Zhang, Jieqiong; Walter, Johannes C.

doi:10.1016/j.dnarep.2014.03.018

Cited by 178 publications

(198 citation statements)

References 76 publications

(139 reference statements)

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“…In this regard, our work highlights a substantial difference between the current proposed models of ICL repair and a modified model consistent with our data (Fig 6; Raschle et al , 2008; Zhang & Walter, 2014). The fundamental predictions of our model are relevant to ICL repair at a single fork, or to the converging fork model.…”

Section: Discussionsupporting

confidence: 83%

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

et al. 2017

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During replication‐coupled DNA interstrand crosslink (ICL) repair, the XPF‐ERCC1 endonuclease is required for the incisions that release, or “unhook”, ICLs, but the mechanism of ICL unhooking remains largely unknown. Incisions are triggered when the nascent leading strand of a replication fork strikes the ICL. Here, we report that while purified XPF‐ERCC1 incises simple ICL‐containing model replication fork structures, the presence of a nascent leading strand, modelling the effects of replication arrest, inhibits this activity. Strikingly, the addition of the single‐stranded DNA (ssDNA)‐binding replication protein A (RPA) selectively restores XPF‐ERCC1 endonuclease activity on this structure. The 5′–3′ exonuclease SNM1A can load from the XPF‐ERCC1‐RPA‐induced incisions and digest past the crosslink to quantitatively complete the unhooking reaction. We postulate that these collaborative activities of XPF‐ERCC1, RPA and SNM1A might explain how ICL unhooking is achieved in vivo.

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Section: Discussionsupporting

confidence: 83%

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

et al. 2017

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“…This DNA replication-dependent ICL repair system relies on the FA proteins, including the XPF/FANCQ-bound SLX4/FANCP, and the depletion of FAN1 or MUS81 alone did not have any effect on the repair of the ICL lesions (Raschle et al 2008;Knipscheer et al 2009;Douwel et al 2014). This and the previous studies stress the role of the XPF-ERCC1-SLX4 complex as the essential nuclease for ICL unhooking (Bhagwat et al 2009;Kim et al 2013;Douwel et al 2014;Hodskinson et al 2014) but leave open the possibility that the other ICL repair nucleases, including SLX4-associated MUS81 and SLX1 as well as FAN1, may possess redundant ICL processing activities or act on structures other than the dual convergent fork during ICL repair (for review, see Zhang and Walter 2014).…”

mentioning

confidence: 99%

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

et al. 2016

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Deficiency of FANCD2/FANCI-associated nuclease 1 (FAN1) in humans leads to karyomegalic interstitial nephritis (KIN), a rare hereditary kidney disease characterized by chronic renal fibrosis, tubular degeneration, and characteristic polyploid nuclei in multiple tissues. The mechanism of how FAN1 protects cells is largely unknown but is thought to involve FAN1's function in DNA interstrand cross-link (ICL) repair. Here, we describe a Fan1-deficient mouse and show that FAN1 is required for cellular and organismal resistance to ICLs. We show that the ubiquitinbinding zinc finger (UBZ) domain of FAN1, which is needed for interaction with FANCD2, is not required for the initial rapid recruitment of FAN1 to ICLs or for its role in DNA ICL resistance. Epistasis analyses reveal that FAN1 has cross-link repair activities that are independent of the Fanconi anemia proteins and that this activity is redundant with the 5 ′ -3 ′ exonuclease SNM1A. Karyomegaly becomes prominent in kidneys and livers of Fan1-deficient mice with age, and mice develop liver dysfunction. Treatment of Fan1-deficient mice with ICL-inducing agents results in pronounced thymic and bone marrow hypocellularity and the disappearance of c-kit + cells. Our results provide insight into the mechanism of FAN1 in ICL repair and demonstrate that the Fan1 mouse model effectively recapitulates the pathological features of human FAN1 deficiency.

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“…Following the accumulation of the FA core complex to an ICL, monoubiquitylation of the FANCD2-FANCI heterodimer by the E3 ubiquitin ligase FANCL promotes its loading on chromatin. This ubiquitination event is central to the recruitment of multiple downstream effectors: the nuclease complexes that promote ICL unhooking via DNA incision, the polymerases that promote TLS and the HR proteins that promote DSB repair (Zhang & Walter 2014). TLS polymerases enable replication by bypassing a lesion on one DNA strand while HR drives repair on the second parental strand…”

Section: Role Of Brca2 In Replication Forks Processingmentioning

confidence: 99%

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

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Mechanism and regulation of incisions during DNA interstrand cross-link repair

Cited by 178 publications

References 76 publications

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

RPA activates the XPF ‐ ERCC 1 endonuclease to initiate processing of DNA interstrand crosslinks

Fan1 deficiency results in DNA interstrand cross-link repair defects, enhanced tissue karyomegaly, and organ dysfunction

BRCA2 functions: from DNA repair to replication fork stabilization

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