Abstract
The prominent role of Fanconi anemia (FA) proteins involves homologous recombination (HR) repair. Poly[ADP-ribose] polymerase1 (PARP1) functions in multiple cellular processes including DNA repair and PARP inhibition is an emerging targeted therapy for cancer patients deficient in HR. Here we show that PARP1 activation in hematopoietic stem and progenitor cells (HSPCs) in response to genotoxic or oxidative stress attenuates HSPC exhaustion. Mechanistically, PARP1 controls the balance between HR and non-homologous end joining (NHEJ) in double strand break (DSB) repair by preventing excessive NHEJ. Disruption of the FA core complex skews PARP1 function in DSB repair and led to hyper-active NHEJ in Fanca−/− or Fancc−/− HSPCs. Re-expression of PARP1 rescues the hyper-active NHEJ phenotype in Brca1−/−Parp1−/− but less effective in Fanca−/−Parp1−/− cells. Inhibition of NHEJ prevents myeloid/erythroid pathologies associated with synthetic lethality. Our results suggest that hyper-active NHEJ may select for “synthetic lethality” resistant and pathological HSPCs.
Highlights
Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and malignancies including leukemia and solid cancers[1,2,3,4]
No overt leukemia was observed in both NU7026- and vehicle-injected mice. These results indicate that inhibition of non-homologous end-joining (NHEJ) prevents myeloid and erythroid pathologies associated with synthetic lethality in Fanca−/−Parp1−/− double knockout (DKO) hematopoietic stem and progenitor cells (HSPCs) and suggest that hyper-active NHEJ may select for synthetic lethality resistant and pathological HSPCs, which were pre-leukemic in nature
We demonstrate that the FA pathway is required for Poly (ADP-ribose) polymerase 1 (PARP1) function in regulation of homologous recombination (HR)-NHEJ balance in double-stranded break (DSB) repair and inhibition of NHEJ prevents myeloid and erythroid pathologies in the context of synthetic lethality
Summary
Fanconi anemia (FA) is a genetic disorder associated with bone marrow (BM) failure and malignancies including leukemia and solid cancers[1,2,3,4]. Another similar study shows that inhibition of the NHEJ ligase, LIG4, ameliorates the FA phenotype, but has no effect on BRCA1 deficiency[16] It appears the FA pathway may act to prevent inappropriate recruitment of NHEJ factors to sites of DNA damage. Using mice deleted for the FA core complex genes encoding Fanca and Fancc, we demonstrate that PARP1 coordinates with the FA pathway to prevent excessive NHEJ in stressed HSPCs. we employed two lines of synthetic-lethality murine models to show that hyper-active NHEJ resulting from synthetic lethality selects for resistant and pathological HSPCs and that inhibition of NHEJ ameliorates hematological pathologies associated with synthetic lethality
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