title: MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice.
abstract: Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase.
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA.
authors: Arun
authors: A
authors: Gupta
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
authors: Clayton R
authors: CR
authors: Hunt
authors: Muralidhar L
authors: ML
authors: Hegde
authors: Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Sharmistha
authors: S
authors: Chakraborty
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Sharmistha
authors: S
authors: Chakraborty
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
authors: Durga
authors: D
authors: Udayakumar
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
authors: Nobuo
authors: N
authors: Horikoshi
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Mayank
authors: M
authors: Singh
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Deepti B
authors: DB
authors: Ramnarain
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Walter N
authors: WN
authors: Hittelman
authors: Department of Biochemistry, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Sarita
authors: S
authors: Namjoshi
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors: Aroumougame
authors: A
authors: Asaithamby
authors: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors: Tapas K
authors: TK
authors: Hazra
authors: Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, OH 43210, USA.
authors: Thomas
authors: T
authors: Ludwig
authors: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA.
authors: Raj K
authors: RK
authors: Pandita
authors: Department of Biochemistry, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors: Jessica K
authors: JK
authors: Tyler
authors: Deparment of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO 63108, USA; Department of Radiation Oncology, The Houston Methodist Research Institute, Houston, TX 77030, USA. Electronic address: tpandita@houstonmethodist.org.
authors: Tej K
authors: TK
authors: Pandita
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism*; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D059585:G1 Phase Cell Cycle Checkpoints; D059565:G2 Phase Cell Cycle Checkpoints; D057809:HEK293 Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D059767:Recombinational DNA Repair; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D047908:Intracellular Signaling Peptides and Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; D064007:Ataxia Telangiectasia Mutated Proteins