RETRACTED: Cockayne Syndrome A and B Proteins Differentially Regulate Recruitment of Chromatin Remodeling and Repair Factors to Stalled RNA Polymerase II In Vivo

Abstract

Restoration of UV-inhibited transcription requires removal of transcription-blocking DNA lesions by transcription-coupled repair (TCR). In mammals, TCR is dependent on CSA and CSB proteins; however, their functions are largely unknown. Here, we analyzed the composition of UV-stalled transcription elongation complexes from human cells. We show that CSB and CSA display differential roles in recruitment of TCR-specific factors and that assembly for TCR occurs without disruption of the UV-stalled RNA polymerase II (RNAPIIo). CSB fulfills a key role as a coupling factor to attract histone acetyltransferase p300, nucleotide excision repair (NER) proteins, and CSA-DDB1 E3-ubiquitin ligase complex with the COP9 signalosome. CSA is dispensable for attraction of NER proteins to lesion-stalled RNAPIIo, yet in cooperation with CSB is required to recruit XAB2, the nucleosomal binding protein HMGN1, and TFIIS. These results give insight into the nature and order of molecular events that take place during TCR in the context of chromosomal DNA.

Transcription-coupled nucleotide excision repair in mammalian cells: molecular mechanisms and biological effects

“…In response to UV, the COP9 signalosome (CSN) was found to associate with the CSA complex resulting in the deneddylation of Cullin 4A and in the inactivation of the ubiquitin ligase activity of the CSA complex at least at the early times after UV irradiation. These data suggest that the CSA (E3-ub ligase) complex when engaged in TC-NER is an inactive ubiquitin ligase [40,41].…”

“…XAB2 is an essential TPRs-(tetratricopeptide repeats) containing protein involved in pre-mRNA splicing and transcription, and has been identified as an XPA binding protein and might function as a scaffolding factor for protein complex formation in TC-NER [42]. In addition to XPA, XAB2 interacts with chromatin bound stalled RNAPIIo complex in a UV-and CS-dependent manner [41]. In agreement with these data, Tanaka and coworkers [43] showed in a recent study that XAB2 interacts with RNAPIIo and that this interaction is enhanced after DNA damage.…”

The role of CSA in the response to oxidative DNA damage in human cells

“…Following UV irradiation, CSA translocates to the nuclear matrix by a CSB-dependent mechanism (Kamiuchi et al, 2002), but these proteins display differential roles in recruitment of chromatin remodelling and repair factors to stalled RNA polymerase II in vivo (Fousteri et al, 2006). CSB-dependent translocation of CSA is also observed following H 2 O 2 , but not on treatment with alkylating agent, and is independent of XPA and XPC, indicating the TCRspecific nature of this response (Kamiuchi et al, 2002).…”

DNARepair: Disorders

“…In this case the XPC protein is dispensable, and the recognition signal in this "transcription-coupled repair" is thought to derive from ribonucleic acid (RNA) polymerase molecules stalled at damaged sites (Figure 1) (Fousteri and Mullenders, 2008). The two proteins defective in patients with CS, namely CSA and CSB, are required to displace the stalled RNA polymerase and recruit the proteins involved in the later steps of NER (Fousteri et al, 2006). The clinical features of CS (Figure 2c) include dwarfism with severe physical and mental retardation, progressive neurological and retinal degeneration, ataxic gait, deafness and sun sensitivity, but again no pigmentation changes or skin cancer (Nance and Berry, 1992).…”