Cell reportsJan 17, 2026

Genetic interactions in the DNA repair system responding to natural damage and radiation

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 18, 2026

Abstract

A large-scale CRISPR-Cas9 screen targeting 461 DNA repair genes identified thousands of genetic interactions under various conditions.

The study examined over 100,000 gene combinations to understand DNA damage response pathways.
A synthetic lethal relationship was validated between the genes MRE11A and UBR5.
Ku70/80 was found to play a role in preventing unwanted nuclease activity at telomeres.
Co-disruption of CYREN and PARG revealed an ionizing radiation-specific vulnerability.
A connection was identified between CYREN-mediated radioresistance and innate immunity.

Simplified

Genomic integrity relies on a complex network of DNA damage response (DDR) pathways that repair endogenous and exogenous lesions, yet how individual factors operate within this broader landscape remains unclear. We performed a large-scale combinatorial CRISPR-Cas9 knockout screen targeting 461 DNA repair genes, disrupting over 100,000 gene combinations under basal conditions and after ionizing radiation (IR). This approach uncovered thousands of genetic interactions spanning pathways that respond to endogenous damage and those specific to double-strand break repair. From this dataset, we validated both positive and negative interactions under basal and irradiated conditions, including a synthetic lethal relationship between MRE11A and the E3 ligase UBR5, a role for Ku70/80 in preventing unscheduled nuclease activity at telomeres, an IR-specific vulnerability upon co-disruption of CYREN and PARG, and a link between CYREN-mediated radioresistance and innate immunity. This resource enables mechanistic insight and reveals therapeutic vulnerabilities in DNA-repair-deficient cancers.

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Funding

Competing interests

Declaration of interests The authors declare no conflicts of interest.

PubMed

Genetic interactions in the DNA repair system responding to natural damage and radiation

Abstract

Full Text

Funding

Competing interests

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