REV7 counteracts DNA double-strand break resection and affects PARP inhibition

Abstract

Summary Error-free repair of DNA double-strand breaks (DSB) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway1. In the absence of BRCA1-mediated HR, administration of PARP inhibitors induces synthetic lethality of tumor cells of patients with breast or ovarian cancers2,3. Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration4. Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases5. In particular, little is known about BRCA1-independent restoration of HR. Here, we show that loss of REV7 (also known as MAD2L2) re-establishes CtIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX-MDC1-RNF8-RNF168-53BP1 chromatin pathway, and appears to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance6. Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining (NHEJ) during immunoglobulin class switch recombination. Our results reveal an unexpected critical function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase

“…ATDC is highly expressed in many tumor types, binds to the DNA repair factor RNF8 and thus may be a determinant of resistance to both cytotoxic chemotherapy and ionizing radiation. RNF8 is required for robust DNA DSB repair, is expressed in many tumors, and appears to participate in acquired resistance to PARP inhibition (COSMIC (Catalogue of Somatic Mutations in Cancer)) (31). The identification of this novel interaction between ATDC and RNF8 establishes a new mechanism whereby ATDC and RNF8 could function in a coordinate manner to produce resistance to DNA damage-based anticancer therapies.…”

TPP1 Blocks an ATR-Mediated Resection Mechanism at Telomeres

“…Whereas these events closely follow the paradigm for DSB resection established in budding yeast (Mimitou and Symington, 2008;Zhu et al, 2008), the control of resection in mammalian cells additionally involves a negative regulator, Rif1, which associates with 53BP1 at sites of DNA damage (Chapman et al, 2013;Di Virgilio et al, 2013;Feng et al, 2013;Escribano-Diaz et al, 2013;Zimmermann et al, 2013). In G1, Rif1 promotes non-homologous end joining (NHEJ) by limiting DSB resection through its interaction with Rev7/MAD2L2 (Xu et al, 2015;Boersma et al, 2015). In S/G2, BRCA1 prevents Rif1 from acting at DSBs, allowing the formation of 3' overhangs and promoting HDR on sister chromatids (reviewed in (Panier and Boulton, 2014;Panier and Durocher, 2013;Zimmermann and de Lange, 2014)).…”

Rev7/Mad2B plays a critical role in the assembly of a functional mitotic spindle

“…Besides its role in TLS, Rev7 was initially believed to be a SAC protein like Mad2 15 ; however, it was later described as an APC/C inhibitor but surprisingly not a SAC protein. [16][17][18] Further adding to its complex nature, several recent reports have suggested additional functions such as upregulation of Elk-1 target genes in response to DNA damage, 19 epithelialmesenchymal transdifferentiation mediated by TCF4, 22 central nervous system development, 23 DNA repair at telomeres, 33 DNA double-strand break resection, 34 cell cycle regulation 20 and more importantly regulation during metaphase. 21,24 In this study we attempted to define the mitotic function(s) of Rev7.…”