Transcription-coupled DNA-protein crosslink repair by CSB and CRL4^CSA-mediated degradation

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• DNA-protein crosslinks (DPCs) are cytotoxic lesions that stall DNA replication.
• The role of DPCs in transcription and their repair mechanisms remain largely unknown.

Purpose of the Study:

• To investigate the impact of DPCs on transcription.
• To elucidate the repair pathways for transcription-blocking DPCs.

Main Methods:

• Investigated DPC effects on RNA polymerase II transcription.
• Identified repair factors involved in DPC removal from active genes.
• Utilized genetic and biochemical approaches to dissect the TC-DPC repair pathway.

Main Results:

• DPCs significantly impede RNA polymerase II-mediated transcription.
• A novel transcription-coupled DPC (TC-DPC) repair pathway preferentially repairs DPCs in active genes.
• TC-DPC repair involves CSB and CSA but not UVSSA or XPA, indicating a non-canonical TC-NER mechanism.
• This pathway is independent of SPRTN and mediated by CRL4^CSA and the proteasome.

Conclusions:

• DPCs pose a significant threat to transcription.
• Cells employ a specialized TC-DPC repair pathway to resolve DPCs in actively transcribed genes.
• This mechanism ensures the integrity of transcription by removing DNA-protein crosslinks.