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

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(S)S). 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(S)S, 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.

• Authors: 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
• Journal: Nature genetics (Nat Genet) Vol. 44 Issue 5 Pg. 598-602 (May 2012) ISSN: 1546-1718 [Electronic] United States
• PMID: 22466611 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Chromatin
• Poly-ADP-Ribose Binding Proteins
• RNA, Small Interfering
• UVSSA protein, human
• Ubiquitin
• RNA Polymerase II
• USP7 protein, human
• Ubiquitin Thiolesterase
• Ubiquitin-Specific Peptidase 7
• DNA Helicases
• ERCC6 protein, human
• DNA Repair Enzymes

Topics

• Carrier Proteins (antagonists & inhibitors, genetics, metabolism)
• Cells, Cultured
• Chromatin (genetics)
• Cockayne Syndrome (genetics)
• DNA Damage (genetics, radiation effects)
• DNA Helicases (chemistry, genetics)
• DNA Repair (genetics, radiation effects)
• DNA Repair Enzymes (chemistry, genetics)
• Humans
• Immunoprecipitation
• Mutation (genetics)
• Poly-ADP-Ribose Binding Proteins
• Proteomics
• RNA Polymerase II (metabolism)
• RNA, Small Interfering (genetics)
• Transcription, Genetic
• Ubiquitin (metabolism)
• Ubiquitin Thiolesterase (genetics, metabolism)
• Ubiquitin-Specific Peptidase 7
• Ultraviolet Rays