Global signatures of Ribonucleotide Excision Repair deficiency and its therapeutic vulnerabilities
Cancer therapies increasingly exploit DNA repair deficiencies, yet many clinically actionable repair-deficient states remain undetectable because they lack robust biomarkers and are not identifiable through gene-based diagnostics. Here, we show that deficiency of ribonucleotide excision repair (RER), a pathway that removes misincorporated ribonucleotides from genomic DNA, generates a distinct…
Cancer treatments often exploit DNA repair deficiencies, but many states where these pathways are impaired remain undetectable due to a lack of biomarkers and gene-based diagnostic tools. Ribonucleotide excision repair (RER) is a pathway that corrects misincorporated ribonucleotides in genomic DNA. Scientists have now demonstrated that RER deficiency produces a unique genome-wide pattern of mutations, including insertion-deletion events, substitutions, and structural variations.
To identify tumors with RER deficiency, the researchers created a tool called RERDetect, a whole-genome classifier. Applying RERDetect to over 11,000 primary and metastatic cancers, they found a subgroup of tumors with evidence of RER deficiency, with most of these cases showing no detectable genetic mutations in RNASEH2 genes. The scientists discovered that promoter hypermethylation of RNASEH2C was a common cause of RER inactivation.
Cells deficient in RER displayed unique vulnerabilities, such as sensitivity to inhibition of the enzymes EXO1 and FANCM. These findings establish RER deficiency as a new, previously undetected DNA repair-deficient state in cancer, highlighting how distinct mutational signatures can reveal clinically relevant tumor phenotypes that conventional genomic diagnostics might miss.
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