title: PAXX promotes KU accumulation at DNA breaks and is essential for end-joining in XLF-deficient mice.
abstract: Non-homologous end-joining (NHEJ) is the most prominent DNA double strand break (DSB) repair pathway in mammalian cells. PAXX is the newest NHEJ factor, which shares structural similarity with known NHEJ factors-XRCC4 and XLF. Here we report that PAXX is dispensable for physiological NHEJ in otherwise wild-type mice. Yet Paxx-/-mice require XLF and Xlf-/-mice require PAXX for end-ligation. As such, Xlf-/-Paxx-/-mice display severe genomic instability and neuronal apoptosis, which eventually lead to embryonic lethality. Despite their structural similarities, only Xlf-/-cells, but not Paxx-/-cells require ATM/DNA-PK kinase activity for end-ligation. Mechanistically, PAXX promotes the accumulation of KU at DSBs, while XLF enhances LIG4 recruitment without affecting KU dynamics at DNA breaks in vivo. Together these findings identify the molecular functions of PAXX in KU accumulation at DNA ends and reveal distinct, yet critically complementary functions of PAXX and XLF during NHEJ.
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Room 501, New York City, New York 10032, USA.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Room 501, New York City, New York 10032, USA.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Room 501, New York City, New York 10032, USA.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Room 501, New York City, New York 10032, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lee
authors.affiliation: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Institute for Cancer Genetics, Columbia University, 1130 Saint Nicholas Avenue, Room 501, New York City, New York 10032, USA.|Division of Pediatric Oncology, Hematology and Stem Cell Transplantation, Department of Pediatrics, College of Physicians &Surgeons, Columbia University, 1130 Saint Nicholas Avenue, Room 501, New York City, New York 10032, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Zha
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000502:physiology*; D000072481:DNA Ligase ATP / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D005347:Fibroblasts; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D061251:Primary Cell Culture
chemical_list: D004268:DNA-Binding Proteins; C000607896:Lig4 protein, mouse; C519508:XLF protein, mouse; D000072200:Ku Autoantigen; D000072481:DNA Ligase ATP