SUMO and ubiquitin-dependent XPC exchange drives nucleotide excision repair.

Loes Van Cuijk,Gijsbert J Van Belle,Arjan F Theil,Jurgen A Marteijn,Wim Vermeulen,Yasemin Turkyilmaz,Roel C Janssens,Niels Mailand,Sara L Poulsen,Hannes Lans,Adriaan B Houtsmuller,Mariangela Sabatella

doi:10.1038/ncomms8499

Abstract

XPC recognizes UV-induced DNA lesions and initiates their removal by nucleotide excision repair (NER). Damage recognition in NER is tightly controlled by ubiquitin and SUMO modifications. Recent studies have shown that the SUMO-targeted ubiquitin ligase RNF111 promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. However, the exact regulatory function of these modifications in vivo remains elusive. Here we show that RNF111 is required for efficient repair of ultraviolet-induced DNA lesions. RNF111-mediated ubiquitylation promotes the release of XPC from damaged DNA after NER initiation, and is needed for stable incorporation of the NER endonucleases XPG and ERCC1/XPF. Our data suggest that RNF111, together with the CRL4DDB2 ubiquitin ligase complex, is responsible for sequential XPC ubiquitylation, which regulates the recruitment and release of XPC and is crucial for efficient progression of the NER reaction, thereby providing an extra layer of quality control of NER.

Highlights

XPC recognizes UV-induced DNA lesions and initiates their removal by nucleotide excision repair (NER)
The recent identification of RNF111 as a SUMO-targeted ubiquitin ligases (STUbLs) involved in UVinduced ubiquitylation of XPC21 has added another level of complexity to the ubiquitin-dependent regulation of this DNA damage sensor, as previously CRL4DDB2 was identified as an E3-ligase complex acting on XPC17
Whereas CRL4DDB2-induced ubiquitylation has been suggested to increase XPC DNA-binding affinity in vitro[17], we provide evidence that RNF111 and its cognate E2—UBC13—are required for efficient release of XPC from UV-lesions, which permits the progress of the NER reaction

Summary

Introduction

XPC recognizes UV-induced DNA lesions and initiates their removal by nucleotide excision repair (NER). Recent studies have shown that the SUMO-targeted ubiquitin ligase RNF111 promotes K63-linked ubiquitylation of SUMOylated XPC after DNA damage. RNF111-mediated ubiquitylation promotes the release of XPC from damaged DNA after NER initiation, and is needed for stable incorporation of the NER endonucleases XPG and ERCC1/XPF. Homozygous Arkadia mutants are non-viable since they fail to form the regulatory primitive node, which is crucial during early gastrulation This problem in the development of the mouse embryo is most likely caused by the loss of the ubiquitin ligase activity of RNF111 that promotes transforming growth factor-b signalling[22,23]. We show that RNF111 is not essential for GG-NER, it strongly enhances the repair reaction by stimulating the release of XPC from damaged DNA, thereby enabling the progress of the NER reaction by recruitment of the endonucleases XPG and XPF/ ERCC1

Methods

Results

Conclusion