Journal Article

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

van Gent, Dik C., Nieuwland, Marja, Rottenberg, Sven, Brandsma, Inger, Gogola, Ewa, van den Broek, Bram, Celie, Patrick H. N., Boulton, Simon J., Chen, Junjie, Kersbergen, Ariena, Yuan, Jingsong, Sol, Wendy, de Rink, Iris, Pieterse, Mark, Bouwman, Peter, Barazas, Marco, Xu, Guotai, Warmerdam, Daniël, de Ronde, Jorma, Bartek, Jiri, Mistrik, Martin, Jalink, Kees, Schouten, Philip C., Jonkers, Jos, Salman, Ahmed, Watanabe, Kenji, Chapman, J. Ross, Bartkova, Jirina, Borst, Piet, Jaspers, Janneke E.

2015

Overview

Loss of REV7 is shown to regulate end resection of double-stranded DNA breaks in BRCA1-deficient cells, leading to PARP inhibitor resistance and restoration of homologous recombination; REV7 dictates pathway choice in BRCA1-deficient cells and during immunoglobulin class switching. MAD2L2/REV7 promotes genome integrity DNA polymerase ζ, composed of REV3, REV7 and an associated factor, REV1, mediates a type of DNA repair involving translesion synthesis, and hence its activity is highly mutagenic. Two studies exploring the DNA damage response have converged on REV7 (also known as MAD2L2) as a factor that, by itself, can promote maintenance of genome integrity. Several protective mechanisms that prevent telomere ends being recognized as a double-strand breaks (DSBs) and triggering an inappropriate DNA damage response were known. Jacqueline Jacobs and colleagues now show that REV7/MAD2L2 suppresses homology-dependent repair at deprotected telomeres and at irradiation-induced DSBs by inhibiting resection of the 5′ end. As a consequence, the ends are shunted into the non-homologous end-joining pathway. Sven Rottenberg and colleagues came to a similar conclusion by studying the development of resistance to PARP inhibitors. They found that REV7/MAD2L2 dictates pathway choice in BRCA-deficient cells and during immunoglobulin class switching. Error-free repair of DNA double-strand breaks (DSBs) is achieved by homologous recombination (HR), and BRCA1 is an important factor for this repair pathway 1 . In the absence of BRCA1-mediated HR, the administration of PARP inhibitors induces synthetic lethality of tumour cells of patients with breast or ovarian cancers 2 , 3 . Despite the benefit of this tailored therapy, drug resistance can occur by HR restoration 4 . Genetic reversion of BRCA1-inactivating mutations can be the underlying mechanism of drug resistance, but this does not explain resistance in all cases 5 . In particular, little is known about BRCA1-independent restoration of HR. Here we show that loss of REV7 (also known as MAD2L2) in mouse and human cell lines re-establishes CTIP-dependent end resection of DSBs in BRCA1-deficient cells, leading to HR restoration and PARP inhibitor resistance, which is reversed by ATM kinase inhibition. REV7 is recruited to DSBs in a manner dependent on the H2AX–MDC1–RNF8–RNF168–53BP1 chromatin pathway, and seems to block HR and promote end joining in addition to its regulatory role in DNA damage tolerance 6 . Finally, we establish that REV7 blocks DSB resection to promote non-homologous end-joining during immunoglobulin class switch recombination. Our results reveal an unexpected crucial function of REV7 downstream of 53BP1 in coordinating pathological DSB repair pathway choices in BRCA1-deficient cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13 / 13/1 / 13/106 / 13/109 / 13/31 / 13/44 / 13/51 / 13/89 / 14 / 631/337/1427/2122 / 631/337/1427/2190 / 631/337/149 / 631/67/1059/2326 / 64 / 64/110 / Adaptor Proteins, Signal Transducing / Analysis / Animals / Ataxia Telangiectasia Mutated Proteins - antagonists & inhibitors / Ataxia Telangiectasia Mutated Proteins - metabolism / Automated teller machines / BRCA1 Protein - deficiency / BRCA1 Protein - genetics / BRCA1 Protein - metabolism / Breast cancer / Cell Cycle Proteins / Cell Line / Chromatin - metabolism / Chromosomal Proteins, Non-Histone - metabolism / Defects / Deoxyribonucleic acid / DNA / DNA Breaks, Double-Stranded / DNA damage / DNA polymerases / DNA repair / DNA-Binding Proteins - metabolism / Drug resistance / Drug Resistance, Neoplasm - genetics / Gene expression / Genetic research / Histones - metabolism / Humanities and Social Sciences / Humans / Immunoglobulin Class Switching - genetics / Intracellular Signaling Peptides and Proteins - metabolism / Ionizing radiation / letter / Mad2 Proteins - deficiency / Mad2 Proteins - genetics / Mad2 Proteins - metabolism / Mice / multidisciplinary / Nuclear Proteins - metabolism / Poly(ADP-ribose) Polymerase Inhibitors / Proteins / Recombinational DNA Repair / Rodents / Science / Telomeres / Trans-Activators - metabolism / Tumor Suppressor p53-Binding Protein 1 / Tumors / Ubiquitin-Protein Ligases - metabolism