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MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice

Arun Gupta1, Clayton R Hunt2, Muralidhar L Hegde

  • 1Deparment 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.

Cell Reports
|June 24, 2014
PubMed

Insights

DNA double-strand breaks trigger ATM-dependent MOF phosphorylation, crucial for DNA repair pathway choice. This phosphorylation regulates 53BP1 and BRCA1 recruitment, impacting homologous recombination repair and cell survival.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cell-cycle phase critically influences DNA double-strand break (DSB) repair pathway selection between nonhomologous end-joining (NHEJ) and homologous recombination (HR).
  • Understanding the regulatory mechanisms governing this choice is essential for comprehending genome stability.

Purpose of the Study:

  • To investigate the role of MOF (histone H4 acetyl-transferase) phosphorylation in response to DSBs.
  • To elucidate how MOF phosphorylation influences the choice between NHEJ and HR repair pathways during specific cell-cycle phases.

Main Methods:

  • Analysis of ATM-dependent MOF phosphorylation (p-T392-MOF) at DSB sites.
  • Colocalization studies of phosphorylated MOF with DNA repair markers (γ-H2AX, ATM, 53BP1).
  • Assessment of DNA repair efficiency and protein recruitment in wild-type and MOF-T392A mutant cells across different cell-cycle phases.

Main Results:

  • DSBs induce ATM-dependent MOF phosphorylation at T392, with p-T392-MOF localizing to DSB foci.
  • Mutation of MOF-T392 impedes DNA repair in S and G2 phases but not G1.
  • MOF-T392A expression alters 53BP1 and BRCA1 recruitment to DSBs, impairing homologous recombination repair and cell survival.

Conclusions:

  • ATM-mediated phosphorylation of MOF at T392 is a key regulator of DSB repair pathway choice in S/G2 phase cells.
  • Phosphorylated MOF modulates 53BP1 function, facilitating the recruitment of HR repair proteins.
  • This uncovers a novel regulatory role for MOF in ensuring accurate DNA repair during specific cell-cycle stages.

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