MOF and H4 K16 Acetylation Play Important Roles in DNA Damage Repair by Modulating Recruitment of DNA Damage Repair Protein Mdc1
- 1 November 2010
- journal article
- Published by Taylor & Francis Ltd in Molecular and Cellular Biology
- Vol. 30 (22), 5335-5347
- https://doi.org/10.1128/mcb.00350-10
Abstract
MOF (MYST1) is the major enzyme to catalyze acetylation of histone H4 lysine 16 (K16) and is highly conserved through evolution. Using a conditional knockout mouse model and the derived mouse embryonic fibroblast cell lines, we showed that loss of Mof led to a global reduction of H4 K16 acetylation, severe G(2)/M cell cycle arrest, massive chromosome aberration, and defects in ionizing radiation-induced DNA damage repair. We further showed that although early DNA damage sensing and signaling by ATM were normal in Mof-null cells, the recruitment of repair mediator protein Mdc1 and its downstream signaling proteins 53bp1 and Brca1 to DNA damage foci was completely abolished. Mechanistic studies suggested that Mof-mediated H4 K16 acetylation and an intact acidic pocket on H2A.X were essential for the recruitment of Mdc1. Removal of Mof and its associated proteins phenocopied a charge-neutralizing mutant of H2A.X. Given the well-characterized H4-H2A trans interactions in regulating higher-order chromatin structure, our study revealed a novel chromatin-based mechanism that regulates the DNA damage repair process.This publication has 56 references indexed in Scilit:
- Two Mammalian MOF Complexes Regulate Transcription Activation by Distinct MechanismsMolecular Cell, 2009
- MYST family histone acetyltransferases take center stage in stem cells and developmentBioEssays, 2009
- PTIP Regulates 53BP1 and SMC1 at the DNA Damage SitesPublished by Elsevier BV ,2009
- RAD18 transmits DNA damage signalling to elicit homologous recombination repairNature, 2009
- Crosstalk between histone modifications during the DNA damage responseTrends in Cell Biology, 2009
- The H4 Tail Domain Participates in Intra- and Internucleosome Interactions with Protein and DNA during Folding and Oligomerization of Nucleosome ArraysMolecular and Cellular Biology, 2009
- Mof (MYST1 or KAT8) Is Essential for Progression of Embryonic Development Past the Blastocyst Stage and Required for Normal Chromatin ArchitectureMolecular and Cellular Biology, 2008
- 30 nm Chromatin Fibre Decompaction Requires both H4-K16 Acetylation and Linker Histone EvictionJournal of Molecular Biology, 2008
- Human Rvb1/Tip49 Is Required for the Histone Acetyltransferase Activity of Tip60/NuA4 and for the Downregulation of Phosphorylation on H2AX after DNA DamageMolecular and Cellular Biology, 2008
- The Mammalian Ortholog of Drosophila MOF That Acetylates Histone H4 Lysine 16 Is Essential for Embryogenesis and OncogenesisMolecular and Cellular Biology, 2008