The nuclease EXO1 promotes genomic instability by degrading nascent DNA in BRCA-proficient cells

Area of Science:

• Genetics
• Molecular Biology
• Cancer Research

Background:

• DNA repair genes, like BRCA1 and BRCA2, are tumor suppressors; their inactivation leads to cancer.
• Defects in homologous recombination repair and nascent DNA degradation by EXO1 and MRE11 are linked to carcinogenesis.
• Most tumors retain BRCA pathway proficiency.

Purpose of the Study:

• To investigate the role of EXO1 in BRCA-proficient tumors.
• To determine if EXO1 overexpression contributes to genomic instability.
• To identify novel mechanisms of carcinogenesis in common cancers.

Main Methods:

• Analysis of EXO1 expression levels in tumor samples.
• In vitro studies to assess EXO1 activity in DNA repair.
• Assays measuring DNA double-strand breaks and replication fork stability.

Main Results:

• EXO1 is overexpressed in a significant subset of tumors.
• Overexpressed EXO1 promotes nascent DNA degradation at ssDNA gaps and reversed forks in BRCA-proficient cells.
• This degradation, mediated by MRE11 cooperation, leads to increased double-strand breaks and sensitivity to genotoxic agents.

Conclusions:

• Increased EXO1 activity is a mechanism of genomic instability.
• This mechanism mimics BRCA pathway inactivation but is more prevalent in tumors.
• EXO1 overexpression represents a potential therapeutic target in a broader range of cancers.