UV-sensitive syndrome protein UVSSA recruits USP7 to regulate transcription-coupled repair

Petra Schwertman, Anna Lagarou, Dick H.W. Dekkers, Anja Raams, Adriana C. Van Der Hoek, Charlie Laffeber, Jan H.J. Hoeijmakers, Jeroen A.A. Demmers, Maria Fousteri, Wim Vermeulen, Jurgen A. Marteijn

Research output: Contribution to journalArticlepeer-review

195 Citations (Scopus)

Abstract

Transcription-coupled nucleotide-excision repair (TC-NER) is a subpathway of NER that efficiently removes the highly toxic RNA polymerase II blocking lesions in DNA. Defective TC-NER gives rise to the human disorders Cockayne syndrome and UV-sensitive syndrome (UV SS). NER initiating factors are known to be regulated by ubiquitination. Using a SILAC-based proteomic approach, we identified UVSSA (formerly known as KIAA1530) as part of a UV-induced ubiquitinated protein complex. Knockdown of UVSSA resulted in TC-NER deficiency. UVSSA was found to be the causative gene for UV SS, an unresolved NER deficiency disorder. The UVSSA protein interacts with elongating RNA polymerase II, localizes specifically to UV-induced lesions, resides in chromatin-associated TC-NER complexes and is implicated in stabilizing the TC-NER master organizing protein ERCC6 (also known as CSB) by delivering the deubiquitinating enzyme USP7 to TC-NER complexes. Together, these findings indicate that UVSSA-USP7-mediated stabilization of ERCC6 represents a critical regulatory mechanism of TC-NER in restoring gene expression.

Original languageEnglish
Pages (from-to)598-602
Number of pages5
JournalNature Genetics
Volume44
Issue number5
DOIs
Publication statusPublished - May 2012
Externally publishedYes

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