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.
Sharma
Girdhar G
GG
Washington University School of Medicine, St. Louis, Missouri 63108, USA.
So
Sairei
S
Gupta
Arun
A
Kumar
Rakesh
R
Cayrou
Christelle
C
Avvakumov
Nikita
N
Bhadra
Utpal
U
Pandita
Raj K
RK
Porteus
Matthew H
MH
Chen
David J
DJ
Cote
Jacques
J
Pandita
Tej K
TK
D000107:Acetylation; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D018922:HL-60 Cells; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D013573:Synaptonemal Complex / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism
D018797:Cell Cycle Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051747:DNA-Activated Protein Kinase; C497263:PRKDC protein, human; D017346:Protein Serine-Threonine Kinases; D008239:Lysine