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MOF and histone H4 acetylation at lysine 16 are critical for DNA damage response and double-strand break repair.

The human MOF gene encodes a protein that specifically acetylates histone H4 at lysine 16 (H4K16ac). Here we show that reduced levels of H4K16ac correlate with a defective DNA damage response (DDR) and double-strand break (DSB) repair to ionizing radiation (IR). The defect, however, is not due to altered expression of proteins involved in DDR. Abrogation of IR-induced DDR by MOF depletion is inhibited by blocking H4K16ac deacetylation. MOF was found to be associated with the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein involved in nonhomologous end-joining (NHEJ) repair. ATM-dependent IR-induced phosphorylation of DNA-PKcs was also abrogated in MOF-depleted cells. Our data indicate that MOF depletion greatly decreased DNA double-strand break repair by both NHEJ and homologous recombination (HR). In addition, MOF activity was associated with general chromatin upon DNA damage and colocalized with the synaptonemal complex in male meiocytes. We propose that MOF, through H4K16ac (histone code), has a critical role at multiple stages in the cellular DNA damage response and DSB repair.

Pubmed ID: 20479123

Authors

  • Sharma GG
  • So S
  • Gupta A
  • Kumar R
  • Cayrou C
  • Avvakumov N
  • Bhadra U
  • Pandita RK
  • Porteus MH
  • Chen DJ
  • Cote J
  • Pandita TK

Journal

Molecular and cellular biology

Publication Data

July 25, 2010

Associated Grants

  • Agency: Canadian Institutes of Health Research, Id: 64289-2
  • Agency: Canadian Institutes of Health Research, Id: 87253-1
  • Agency: NCI NIH HHS, Id: CA 50519
  • Agency: NCI NIH HHS, Id: CA10445
  • Agency: NCI NIH HHS, Id: CA123232
  • Agency: Canadian Institutes of Health Research, Id: MOP-64289
  • Agency: NCI NIH HHS, Id: R01 CA123232
  • Agency: NCI NIH HHS, Id: R01 CA123232-01A1
  • Agency: NCI NIH HHS, Id: R01 CA123232-02
  • Agency: NCI NIH HHS, Id: R01 CA123232-03
  • Agency: NCI NIH HHS, Id: R01 CA123232-04
  • Agency: NCI NIH HHS, Id: R01 CA123232-05
  • Agency: NCI NIH HHS, Id: R01 CA123232-06
  • Agency: NCI NIH HHS, Id: R01 CA129537
  • Agency: NCI NIH HHS, Id: R01 CA129537-01A1
  • Agency: NCI NIH HHS, Id: R01 CA129537-02
  • Agency: NCI NIH HHS, Id: R01 CA129537-03
  • Agency: NCI NIH HHS, Id: R01 CA129537-04
  • Agency: NCI NIH HHS, Id: R01 CA129537-05
  • Agency: NINDS NIH HHS, Id: R01 NS034746
  • Agency: NINDS NIH HHS, Id: R01 NS034746-05
  • Agency: NINDS NIH HHS, Id: R01 NS034746-05S1
  • Agency: NINDS NIH HHS, Id: R01 NS034746-06
  • Agency: NINDS NIH HHS, Id: R01 NS034746-06S1
  • Agency: NCI NIH HHS, Id: R13 CA130756
  • Agency: NCI NIH HHS, Id: R13 CA130756-01
  • Agency: NCI NIH HHS, Id: R13 CA130756-02
  • Agency: NCI NIH HHS, Id: R13 CA130756-03
  • Agency: NCI NIH HHS, Id: R13 CA130756-04
  • Agency: NCI NIH HHS, Id: R13 CA130756-05

Mesh Terms

  • Acetylation
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Cell Cycle Proteins
  • Cell Line
  • Chromatin
  • DNA Breaks, Double-Stranded
  • DNA Damage
  • DNA Repair
  • DNA-Activated Protein Kinase
  • DNA-Binding Proteins
  • Female
  • HL-60 Cells
  • Histone Acetyltransferases
  • Histone Deacetylase Inhibitors
  • Histones
  • Humans
  • Lysine
  • Male
  • Nuclear Proteins
  • Protein-Serine-Threonine Kinases
  • RNA Interference
  • RNA, Small Interfering
  • Synaptonemal Complex
  • Tumor Suppressor Proteins