FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice

Orthwein, Alexandre; Findlay, Steven; Heath, John A.; Luo, Vincent; Malina, Abba; Li, Zhigang; Samiei, Arash; Cheyou, Estelle Simo; Karam, Marc; Bagci, Halil; Rahat, Dolev; Grapton, Damien; Lavoie, Élise G.; Dove, Christian; Khaled, Husam; Mann, Koren K.; Klein, Kathleen; Tabach, Yuval; Côté, Jean‐François; Maréchal, Alexandre; Morin, Théo; Djerir, Billel; Park, Morag M; Kuasne, Hellen

doi:10.1101/365460

Cited by 50 publications

(115 citation statements)

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“…Although structural information on the SHLD2 OB‐folds is currently unavailable, the purified SHLD2 C‐terminus binds to DNA, with a strong preference for ssDNA that is consistent with the binding properties of other OB‐fold proteins . ssDNA binding in vitro is abolished by the same aromatic residue mutations that disable the ability of SHLD2 to suppress HR, underlining ssDNA binding as a key function of SHLD2 .…”

Section: Introductionmentioning

confidence: 62%

Shieldin – the protector of DNA ends

2019

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DNA double‐strand breaks are a threat to genome integrity and cell viability. The nucleolytic processing of broken DNA ends plays a central role in dictating the repair processes that will mend these lesions. Usually, DNA end resection promotes repair by homologous recombination, whereas minimally processed ends are repaired by non‐homologous end joining. Important in this process is the chromatin‐binding protein 53BP1, which inhibits DNA end resection. How 53BP1 shields DNA ends from nucleases has been an enduring mystery. The recent discovery of shieldin, a four‐subunit protein complex with single‐stranded DNA‐binding activity, illuminated a strong candidate for the ultimate effector of 53BP1‐dependent end protection. Shieldin consists of REV7, a known 53BP1‐pathway component, and three hitherto uncharacterized proteins: C20orf196 (SHLD1), FAM35A (SHLD2), and CTC‐534A2.2 (SHLD3). Shieldin promotes many 53BP1‐associated activities, such as the protection of DNA ends, non‐homologous end joining, and immunoglobulin class switching. This review summarizes the identification of shieldin and the various models of shieldin action and highlights some outstanding questions requiring answers to gain a full molecular understanding of shieldin function.

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Section: Introductionmentioning

confidence: 62%

Shieldin – the protector of DNA ends

2019

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“…As 53BP1 works together with the rest of its downstream cofactors to block over-resection of DNA DSBs, loss of any of these proteins partially restores RAD51 filament formation, functional HR and PARP-inhibitor resistance in BRCA1-deficient cells. Notably, whereas recruitment of RIF1, REV7 and SHLD1/2/3 depends on intact 53BP1, losing the downstream proteins does not prevent 53BP1 from forming IRIF [44][45][46][47] . Thus, in the absence of its co-factors, 53BP1 is still bound to DSB-proximal chromatin and therefore might interfere with efficient PALB2 recruitment, especially in BRCA1-deficient settings.…”

Section: Discussionmentioning

confidence: 98%

PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

et al. 2020

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Loss of functional BRCA1 protein leads to defects in DNA double-strand break (DSB) repair by homologous recombination (HR) and renders cells hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibitors used to treat BRCA1/2-deficient cancers. However, upon chronic treatment of BRCA1-mutant cells with PARP inhibitors, resistant clones can arise via several mechanisms, including loss of 53BP1 or its downstream co-factors. Defects in the 53BP1 axis partially restore the ability of a BRCA1-deficient cell to form RAD51 filaments at resected DSBs in a PALB2-and BRCA2-dependent manner, and thereby repair DSBs by HR. Here we show that depleting 53BP1 in BRCA1-null cells restores PALB2 accrual at resected DSBs. Moreover, we demonstrate that PALB2 DSB recruitment in BRCA1/53BP1-deficient cells is mediated by an interaction between PALB2's chromatin associated motif (ChAM) and the nucleosome acidic patch region, which in 53BP1-expressing cells is bound by 53BP1's ubiquitin-directed recruitment (UDR) domain.

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“…However, it remained elusive how the sequential recruitment of these proteins to DSBs inhibits resection because neither of them contains any clear catalytic activity. In a collective search for novel factors involved in HR regulation, several groups recently performed proteomics studies and genome-wide PARPi-resistance CRISPR/Cas9 screens and reported the identification of the Shieldin (SHLD) protein complex as an active inhibitor of resection [64][65][66][67][68][69][70] (Box 2). This complex, comprising REV7, SHLD1, SHLD2, and SHLD3, is recruited to DSBs via SHLD3 in a 53BP1-and RIF1dependent manner.…”

Section: Reactivation Of Hr As Mechanisms Of Parpi Resistancementioning

confidence: 99%

PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

Noordermeer

Attikum

2019

Trends in Cell Biology

342

285

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Poly-(ADP)-ribose polymerase (PARP) inhibition is synthetic lethal with deficiency for homologous recombination (HR), a pathway essential for DNA double-strand break repair. PARP inhibitors (PARPi) therefore hold great promise for the treatment of tumors with disruptive mutations in BRCA1/2 or other HR factors. Unfortunately, PARPi resistance has proved to be a major problem in the clinic. Knowledge about PARPi resistance is expanding quickly, revealing four main mechanisms that alter drug availability, affect (de)PARylation enzymes, restore HR, or restore replication fork stability. We discuss how studies on resistance mechanisms have yielded important insights into the regulation of DNA double-strand break (DSB) repair and replication fork protection, and how these studies could pave the way for novel treatment options to target resistance mechanisms or acquired vulnerabilities. Defective DSB Repair and Cancer Genomic instability is one of the enabling characteristics of tumor development [1]. To maintain genomic integrity, cells are equipped with multiple mechanisms to repair a wide variety of DNA lesions caused by exogenous and endogenous events. One particularly toxic lesion is the DNA double-strand break (DSB; see Glossary). This lesion can be caused by ionizing irradiation and genotoxic chemicals, but can also arise as an intermediate of resolving stalled or collapsed replication forks (replication fork instability) [2]. If left unrepaired or are repaired incorrectly, DSBs can give rise to mutations, deletions, amplifications, and chromosomal translocations, leading to various outcomes such as senescence, cell death, or malignant transformation. Over 30 years ago, Marie-Claire King and colleagues discovered the linkage between familial earlyonset breast cancer and the genomic region 17q21 [3]. We now know that the gene affected is BRCA1, and that mutations in this gene are not only linked to breast cancer but also to familial cases of ovarian cancer and sporadic tumors of different origins [4-7]. BRCA1 is an essential factor in the repair of DSBs via homologous recombination (HR) (see Box 1 for a more detailed overview of DSB repair). Moreover, homozygous loss of BRCA1 is not tolerated during human and mouse embryonic development [8]. This BRCA1 survival-dependency can be partially overcome by concomitant loss of p53 [9]. Importantly, mouse models with mammary gland-specific loss of these genes show increased breast tumor formation [8]. Indeed, in clinical tumor samples, BRCA1 mutations often co-occurbut not alwayswith TP53 mutations [8,10]. Epigenetic silencing of BRCA1 expression via promoter hypermethylation is another way of reducing BRCA1 activity, and this has been shown to occur frequently in tumors [6,11,12]. In addition to aberrations in BRCA1, genes encoding many more factors involved in HR, such as BRCA2, PALB2, and RAD51, are known to be affected in a wide variety of tumors. All these tumors display severe chromosomal instability as a result of deregulated HR, a phenotype referred to as 'BRCAne...

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FAM35A co-operates with REV7 to coordinate DNA double-strand break repair pathway choice

Abstract: # contributed equally to the work Running title: FAM35A is a novel DNA repair factor.

Cited by 50 publications

References 68 publications

Shieldin – the protector of DNA ends

Shieldin – the protector of DNA ends

PALB2 chromatin recruitment restores homologous recombination in BRCA1-deficient cells depleted of 53BP1

PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells

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