UVSSA and USP7: new players regulating transcription-coupled nucleotide excision repair in human cells

Alain Sarasin

doi:10.1186/gm343

Abstract

Transcription-coupled nucleotide excision repair (TC-NER) specifically removes DNA damage located in actively transcribed genes. Defects in TC-NER are associated with several human disorders, including Cockayne syndrome (CS) and ultraviolet (UV)-sensitive syndrome (UVSS). Using exome sequencing, and genetic and proteomic approaches, three recent studies have identified mutations in the UVSSA gene as being responsible for UVSS-A. These findings suggest a new mechanistic model involving UV-stimulated scaffold protein A (UVSSA) and the ubiquitin-specific protease 7 (USP7) in the fate of stalled RNA polymerase II during TC-NER, and provide insights into the diverse clinical features of CS and UVSS.

Highlights

Transcription-coupled nucleotide excision repair (TC-Nucleotide excision repair (NER)) removes DNA damage located in actively transcribed genes
Genetic characterization of the third complementation group of UV-sensitive syndrome (UVSS) patients Three papers published recently in Nature Genetics have reported the isolation of the gene responsible for the UVSS-A complementation group, UV-stimulated scaffold protein A (UVSSA), using three different approaches: exome sequencing of cell lines derived from patients with UVSS-A [7], complementation of the repair defect of UVSS-A cells [8] and stable isotope labeling by amino acids in cell culture (SILAC)-based proteomic isolation of differentially ubiquitinated proteins following UV irradiation [9]
In UVSS-A cells, dephosphorylation of RNA polymerase (Pol) elongating form of RNA Pol II (IIo) is inhibited, as previously found in Cockayne syndrome (CS) cells [8], and the absence of dephosphorylation does not allow the recycling of Pol II for transcription initiation [7]. These findings suggest a new model for UV-induced Transcription-coupled nucleotide excision repair (TC-NER) in which UVSSA and ubiquitin-specific protease 7 (USP7) are crucial for Pol IIo ubiquitination and the resumption of normal transcription

Summary

Introduction

Transcription-coupled nucleotide excision repair (TC-NER) removes DNA damage located in actively transcribed genes. The current model for TC-NER postulates that the pathway is initiated by the arrest of RNA polymerase IIo at a lesion on the transcribed strand of an active gene - a process requiring several factors, including CSA, CSB and XAB2 proteins [1].

Results

Conclusion