Journal Article

Transcription-coupled repair of DNA–protein cross-links depends on CSA and CSB

Zhao, Shubo, Balasubramanian, Shankar, Wondergem, Annelotte P., Carnie, Christopher J., Weickert, Pedro, Esain-Garcia, Isabel, Jackson, Stephen P., Stingele, Julian, Erdenebat, Chimeg, van den Heuvel, Diana, Parnas, Avital, Lam, Simon, Cordes, Jacqueline, Adar, Sheera, Gupta, Vipul, Acampora, Aleida C., Götz, Maximilian J., Melidis, Larry, Luijsterburg, Martijn S., Sczaniecka-Clift, Matylda, Robles, Maria S., D’Alessandro, Giuseppina, Bitensky, Elnatan, Bader, Aldo S., Aygenli, Fatih

2024

Overview

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. Three studies identify a transcription-coupled DNA–protein cross-link repair pathway that depends on the Cockayne syndrome proteins and the proteasome.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/58 / 13/106 / 14 / 14/1 / 14/34 / 14/63 / 38 / 38/22 / 42 / 45 / 45/23 / 631/337/1427 / 631/80/304 / 82/47 / Adducts / Biomedical and Life Sciences / Cancer Research / Cell Biology / Cockayne syndrome / Cockayne Syndrome - genetics / Cockayne Syndrome - metabolism / Cockayne Syndrome - pathology / Crosslinking / Deoxyribonucleic acid / Developmental Biology / DNA / DNA adducts / DNA Adducts - genetics / DNA Adducts - metabolism / DNA biosynthesis / DNA Damage / DNA Helicases - genetics / DNA Helicases - metabolism / DNA Repair / DNA Repair Enzymes - genetics / DNA Repair Enzymes - metabolism / DNA sequencing / DNA-directed RNA polymerase / Excision Repair / Gene mapping / Gene sequencing / Genetic screening / Genomes / Humans / Lesions / Life Sciences / Light effects / Nucleotide excision repair / Nucleotides / Peptide mapping / Poly-ADP-Ribose Binding Proteins - genetics / Poly-ADP-Ribose Binding Proteins - metabolism / Proteasomes / Protein adducts / Proteins / Receptors, Interleukin-17 / Ribonucleic acid / RNA / RNA polymerase / RNA polymerase II / RNA Polymerase II - genetics / RNA Polymerase II - metabolism / Stem Cells / Toxicity / Transcription Factors / Transcription, Genetic / Transcription-coupled repair / Ubiquitin / Ubiquitination / Ultraviolet radiation / Ultraviolet Rays