A CSB-PAF1C axis restores processive transcription elongation after DNA damage repair

Abstract

150)The coordinated transcription of genes involves the regulated release of RNA polymerase II (RNAPII) from promoter-proximal sites into active elongation. DNA lesions in transcribed strands block elongation and induce a strong transcriptional arrest. The transcription-coupled repair (TCR) pathway efficiently removes transcription-blocking DNA lesions, but this is not sufficient to resume transcription. Through proteomics screens, we find that the TCR-specific CSB protein loads the evolutionary conserved PAF1 complex (PAF1C) onto RNAPII in promoter-proximal regions in response to DNA damage. PAF1C is dispensable for TCR-mediated repair, but is essential for recovery of RNA synthesis after UV irradiation, suggesting an uncoupling between DNA repair and transcription recovery. Moreover, we find that PAF1C promotes RNAPII pause release in promoter-proximal regions and subsequently acts as a processivity factor that stimulates transcription elongation throughout genes. Our findings expose the molecular basis for a non-canonical PAF1C-dependent pathway that restores transcription throughout the human genome after genotoxic stress.

Cockayne Syndrome Group B (CSB): The Regulatory Framework Governing the Multifunctional Protein and Its Plausible Role in Cancer

“…In addition, CSB is required for the recruitment of the CSA/DDB1-Cul4A-RBX1 E3 ubiquitin ligase (CRL4 CSA ) in complex with the COP9 signalosome, key NER factors and chromatin modifiers such as p300 histone acetyltransferase and HMGN1 at the site of damage-stalled RNA Pol II [ 14 ]. Upon efficient repair, a role of CSB in transcription recovery from promoter proximal sites, which takes place via a CSB-mediated association of the PAF1 complex with RNAPII, has been also highlighted recently [ 15 ]. Besides the TC-NER repair pathway, CSB plays a role in the repair of oxidative DNA lesions via BER, in interstrand crosslink (ICL) repair, in DNA double-strand break (DSB) repair and checkpoint activation [ 16 , 17 , 18 , 19 , 20 , 21 ].…”