Mapping the Genetic Interaction Network of PARP inhibitor Response

Abstract

Genetic interactions have long informed our understanding of the coordinated proteins and pathways that respond to DNA damage in mammalian cells, but systematic interrogation of the genetic network underlying that system has yet to be achieved. Towards this goal, we measured 147,153 pairwise interactions among genes implicated in PARP inhibitor (PARPi) response. Evaluating genetic interactions at this scale, with and without exposure to PARPi, revealed hierarchical organization of the pathways and complexes that maintain genome stability during normal growth and defined changes that occur upon accumulation of DNA lesions due to cytotoxic doses of PARPi. We uncovered unexpected relationships among DNA repair genes, including context-specific buffering interactions between the minimally characterized AUNIP and BRCA1-A complex genes. Our work thus establishes a foundation for mapping differential genetic interactions in mammalian cells and provides a comprehensive resource for future studies of DNA repair and PARP inhibitors.

FANCJ promotes PARP1 activity during DNA replication that is essential in BRCA1 deficient cells

“…5h ). This finding was similar to the greater than expected loss of viability between FANCJ and BRCA1 dual deletion as compared to each single deletion 18 . Collectively, these findings suggest that loss of PARP1 replication activity due to PARPi, PARP1 deletion or FANCJ deletion is toxic to BRCA1 deficient cells ( Fig.…”

“…Given that XRCC1-deficient cells also gain PARPi resistance with FANCJ loss, we can surmise that canonical trapping is also reduced in this setting. Indeed, PARPi sensitivity in several genetic contexts is reversed by PARP1 deletion consistent with a trapping model 18,[53][54][55] . Likewise, in the context of BRCA1 mutant cells in which residual BRCA function tolerates PARP1 loss, PARPi toxicity can be suppressed by mutations that reduce PARP1 trapping [56][57][58] .…”

“…Finally, while replication speed is also distinct between FANCJ versus BRCA1 deficient cells, a series of cell models revealed that speed can be uncoupled from PARPi toxicity 17 . The contrast between BRCA1 and FANCJ is further supported by a genetic interaction network of PARPi response 18 . Notably, FANCJ loss as compared to other BRCA-Fanconi anemia genes confers the weakest PARPi sensitization phenotype, indicating again the unique role of (which was not certified by peer review) is the author/funder.…”