MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair
- 1 July 2010
- journal article
- research article
- Published by Informa UK Limited in Molecular and Cellular Biology
- Vol. 30 (14), 3582-3595
- https://doi.org/10.1128/mcb.01476-09
Abstract
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.Keywords
This publication has 96 references indexed in Scilit:
- Two Mammalian MOF Complexes Regulate Transcription Activation by Distinct MechanismsMolecular Cell, 2009
- BRIT1/MCPH1 links chromatin remodelling to DNA damage responseNature, 2009
- Histone H4 lysine 16 acetylation regulates cellular lifespanNature, 2009
- Distinct roles of ATR and DNA‐PKcs in triggering DNA damage responses in ATM‐deficient cellsEMBO Reports, 2009
- Screen for DNA-damage-responsive histone modifications identifies H3K9Ac and H3K56Ac in human cellsThe EMBO Journal, 2009
- CBP/p300-mediated acetylation of histone H3 on lysine 56Nature, 2009
- Single-stranded DNA-binding protein hSSB1 is critical for genomic stabilityNature, 2008
- Positional stability of single double-strand breaks in mammalian cellsNature, 2007
- Structural Basis for the Methylation State-Specific Recognition of Histone H4-K20 by 53BP1 and Crb2 in DNA RepairCell, 2006
- The cellular control of DNA double‐strand breaksJournal of Cellular Biochemistry, 2006