TY - JOUR
T1 - Transcription-coupled repair of DNA–protein cross-links depends on CSA and CSB
AU - Carnie, Christopher J.
AU - Acampora, Aleida C.
AU - Bader, Aldo S.
AU - Erdenebat, Chimeg
AU - Zhao, Shubo
AU - Bitensky, Elnatan
AU - van den Heuvel, Diana
AU - Parnas, Avital
AU - Gupta, Vipul
AU - D’Alessandro, Giuseppina
AU - Sczaniecka-Clift, Matylda
AU - Weickert, Pedro
AU - Aygenli, Fatih
AU - Götz, Maximilian J.
AU - Cordes, Jacqueline
AU - Esain-Garcia, Isabel
AU - Melidis, Larry
AU - Wondergem, Annelotte P.
AU - Lam, Simon
AU - Robles, Maria S.
AU - Balasubramanian, Shankar
AU - Adar, Sheera
AU - Luijsterburg, Martijn S.
AU - Jackson, Stephen P.
AU - Stingele, Julian
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024/5
Y1 - 2024/5
N2 - Covalent DNA–protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA–protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes. Consequently, CSB- or CSA-deficient cells fail to efficiently restart transcription after induction of DPCs. In contrast, nucleotide excision repair factors that act downstream of CSB and CSA at ultraviolet light-induced DNA lesions are dispensable. Our study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS.
AB - Covalent DNA–protein cross-links (DPCs) are toxic DNA lesions that block replication and require repair by multiple pathways. Whether transcription blockage contributes to the toxicity of DPCs and how cells respond when RNA polymerases stall at DPCs is unknown. Here we find that DPC formation arrests transcription and induces ubiquitylation and degradation of RNA polymerase II. Using genetic screens and a method for the genome-wide mapping of DNA–protein adducts, DPC sequencing, we discover that Cockayne syndrome (CS) proteins CSB and CSA provide resistance to DPC-inducing agents by promoting DPC repair in actively transcribed genes. Consequently, CSB- or CSA-deficient cells fail to efficiently restart transcription after induction of DPCs. In contrast, nucleotide excision repair factors that act downstream of CSB and CSA at ultraviolet light-induced DNA lesions are dispensable. Our study describes a transcription-coupled DPC repair pathway and suggests that defects in this pathway may contribute to the unique neurological features of CS.
UR - http://www.scopus.com/inward/record.url?scp=85189900026&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41556-024-01391-1
DO - https://doi.org/10.1038/s41556-024-01391-1
M3 - مقالة
C2 - 38600235
SN - 1465-7392
VL - 26
SP - 797
EP - 810
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 5
ER -
