title: Temporal activation of XRCC1-mediated DNA repair is essential for muscle differentiation.
abstract: Transient DNA strand break formation has been identified as an effective means to enhance gene expression in living cells. In the muscle lineage, cell differentiation is contingent upon the induction of caspase-mediated DNA strand breaks, which act to establish the terminal gene expression program. This coordinated DNA nicking is rapidly resolved, suggesting that myoblasts may deploy DNA repair machinery to stabilize the genome and entrench the differentiated phenotype. Here, we identify the base excision repair pathway component XRCC1 as an indispensable mediator of muscle differentiation. Caspase-triggered XRCC1 repair foci form rapidly within differentiating myonuclei, and then dissipate as the maturation program proceeds. Skeletal myoblast deletion of Xrcc1 does not have an impact on cell growth, yet leads to perinatal lethality, with sustained DNA damage and impaired myofiber development. Together, these results demonstrate that XRCC1 manages a temporally responsive DNA repair process to advance the muscle differentiation program.
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Mohammad H
authors.initials: MH
authors.lastname: Al-Khalaf
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital , Ottawa, ON, Canada.
authors.forename: Leanne E
authors.initials: LE
authors.lastname: Blake
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Larsen
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital , Ottawa, ON, Canada.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Bell
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital , Ottawa, ON, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Brunette
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Parks
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Rudnicki
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital , Memphis, TN, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Jeffrey Dilworth
authors.affiliation: Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Megeney
keywords: DNA strand breaks; XRCC1; base excision repair; muscle differentiation