MOF and Histone H4 Acetylation at Lysine 16 Are Critical for DNA Damage Response and Double-Strand Break Repair

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.

Supplemental material for this article may be found at http://mcb.asm.org/.

We thank Fred Alt for SirT2 mouse embryonic fibroblast cells and Tom Misteli for reagents. Thanks are due to Clayton Hunt, Sandeep Burma, Nobuo Horikoshi, and the members of the Pandita laboratory for suggestions and comments and helpful discussion.

This work was supported by grants NIH CA123232 and CA10445 to T.K.P.; CA 50519 to D.C.; and CIHR MOP-64289 to J.C., who is also a Canada Research Chair. N.A. is a CIHR postdoctoral fellow.

We declare that we have no competing financial interests.