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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylation
-
Adaptor Proteins, Signal Transducing
-
Animals
-
Ataxia Telangiectasia Mutated Proteins
-
BRCA1 Protein / genetics
-
BRCA1 Protein / metabolism
-
Cell Cycle / physiology
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cell Proliferation
-
Cells, Cultured
-
Chromosomal Proteins, Non-Histone
-
DNA Damage*
-
DNA Repair*
-
DNA-Binding Proteins / genetics
-
DNA-Binding Proteins / metabolism
-
Fibroblasts / cytology
-
Fibroblasts / physiology
-
Fibroblasts / radiation effects
-
Histone Acetyltransferases / genetics
-
Histone Acetyltransferases / metabolism*
-
Histones / genetics
-
Histones / metabolism*
-
Intracellular Signaling Peptides and Proteins / genetics
-
Intracellular Signaling Peptides and Proteins / metabolism*
-
Mice
-
Mice, Knockout
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism
-
Radiation, Ionizing
-
Signal Transduction / physiology
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism
-
Tumor Suppressor p53-Binding Protein 1
Substances
-
Adaptor Proteins, Signal Transducing
-
BRCA1 Protein
-
Cell Cycle Proteins
-
Chromosomal Proteins, Non-Histone
-
DNA-Binding Proteins
-
Histones
-
Intracellular Signaling Peptides and Proteins
-
MDC1 protein, mouse
-
Trp53bp1 protein, mouse
-
Tumor Suppressor Proteins
-
Tumor Suppressor p53-Binding Protein 1
-
Histone Acetyltransferases
-
Kat8 protein, mouse
-
Ataxia Telangiectasia Mutated Proteins
-
Atm protein, mouse
-
Protein Serine-Threonine Kinases