Transcription-Coupled Repair Promotes the Retention of Mutations in Coding Regions During Replication Stress

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• Replication stress (RS) drives genomic instability in cancer.
• The role of transcription-coupled nucleotide excision repair (TC-NER) in shaping mutation landscapes during RS is not fully understood.

Purpose of the Study:

• To investigate how the TC-NER factor ERCC6 (also known as CSB) influences mutational landscapes under replication stress conditions.
• To elucidate the differential cellular responses and genomic alterations associated with ERCC6 proficiency versus deficiency during RS.

Main Methods:

• Utilized whole-exome sequencing to analyze mutation profiles in ERCC6-proficient and ERCC6-deficient cells under RS.
• Examined DNA damage signaling pathways, including 53BP1-mediated responses.
• Assessed cellular outcomes such as senescence and proliferative recovery.

Main Results:

• ERCC6 deficiency promotes a 53BP1-mediated DNA damage response, leading to senescence.
• ERCC6-proficient cells exhibit distinct genomic alterations, accumulating stress-induced mutations within coding regions of active genes.
• ERCC6-deficient cells accumulate mutations predominantly in intergenic regions.

Conclusions:

• ERCC6 plays a crucial role in maintaining transcriptional continuity during replication stress.
• ERCC6 activity is linked to the biased retention of mutations in coding regions within the surviving cell population.
• This study uncovers a novel connection between TC-NER, mutation distribution, and context-dependent somatic evolution in human cells, impacting tumor heterogeneity.