title: Hyper-active non-homologous end joining selects for synthetic lethality resistant and pathological Fanconi anemia hematopoietic stem and progenitor cells.
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.
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.|Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Wei
authors.initials: W
authors.lastname: Du
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Surya
authors.initials: S
authors.lastname: Amarachintha
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Wilson
authors.affiliation: Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229.|Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229.
authors.forename: Qishen
authors.initials: Q
authors.lastname: Pang
mesh_terms: D000818:Animals; D019313:BRCA1 Protein; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D059766:DNA End-Joining Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005199:Fanconi Anemia / Q000235:genetics; D051856:Fanconi Anemia Complementation Group Proteins / Q000235:genetics* / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D059765:Homologous Recombination / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000378:metabolism*; D000072020:Synthetic Lethal Mutations / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C000605931:Brca1 protein, mouse; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; D025521:Tumor Suppressor Proteins; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1