2. Academic Validation
  3. Uncovering genetic interactions in the DNA repair network in response to endogenous damage and ionizing radiation

Uncovering genetic interactions in the DNA repair network in response to endogenous damage and ionizing radiation

  • Cell Rep. 2026 Jan 27;45(1):116850. doi: 10.1016/j.celrep.2025.116850.
Benjamin Nebenfuehr 1,  Lynn Sanford 2,  Erin R Taylor 1,  Kerri Ball 1,  Catherine E Woods-Killam 1,  Hannah I Ghasemi 1,  Bruce Proctor 3rd 1,  Raquel Ortega 1,  Colin Sempeck 1,  Robin D Dowell 2,  Nausica Arnoult 3
Affiliations

Affiliations

  • 1 University of Colorado Boulder, Department of Molecular, Cellular, and Developmental Biology, Boulder, CO 80309, USA.
  • 2 University of Colorado Boulder, Department of Molecular, Cellular, and Developmental Biology, Boulder, CO 80309, USA; University of Colorado Boulder, BioFrontiers Institute, Boulder, CO 80309, USA.
  • 3 University of Colorado Boulder, Department of Molecular, Cellular, and Developmental Biology, Boulder, CO 80309, USA. Electronic address: [email protected].
PMID: 41546867 DOI: 10.1016/j.celrep.2025.116850
Abstract

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.

Keywords

CP: molecular biology; CRISPR; CYREN; DNA damage; DNA repair; Ku; MRE11; UBR5; combinatorial screen; telomeres.

Figures
Products