Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair

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Abstract

Although the acetylation of histones has a well-documented regulatory role in transcription1,2,3,4, its role in other chromosomal functions remains largely unexplored. Here we show that distinct patterns of histone H4 acetylation are essential in two separate pathways of double-strand break repair. A budding yeast strain with mutations in wild-type H4 acetylation sites shows defects in nonhomologous end joining repair and in a newly described pathway of replication-coupled repair. Both pathways require the ESA1 histone acetyl transferase (HAT), which is responsible for acetylating all H4 tail lysines, including ectopic lysines that restore repair capacity to a mutant H4 tail. Arp4, a protein that binds histone H4 tails and is part of the Esa1-containing NuA4 HAT complex, is recruited specifically to DNA double-strand breaks that are generated in vivo. The purified Esa1–Arp4 HAT complex acetylates linear nucleosomal arrays with far greater efficiency than circular arrays in vitro, indicating that it preferentially acetylates nucleosomes near a break site. Together, our data show that histone tail acetylation is required directly for DNA repair and suggest that a related human HAT complex may function similarly.

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Figure 1: hhf1-10 is hypersensitive to DSBs and addition of a single lysine to hhf1-10 rescues CPT hypersensitivity.
Figure 2: ESA1 is required for H4 tail acetylation and for DSB repair.
Figure 3: Arp4 is recruited to a DSB site in vivo.
Figure 4: NuA4 preferentially acetylates linear nucleosomal arrays.

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Acknowledgements

We thank D. Allis for antibodies to acetylated histone H4; J. Haber for the HO cut site strain; S. Elledge for RNR plasmids; B. Sarapin for help with esa1 mutant construction; and D. Allis, D. Pellman and N. Levin for comments on the manuscript. A.B. was supported by an NIH training grant predoctoral fellowship. P.A.G. is the recipient of a Burroughs Wellcome career development award in Biomedical Sciences. This work was supported by grants from the NIH to P.A.G., M.M.S. and M.F.C.

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Correspondence to Michael F. Christman.

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Bird, A., Yu, D., Pray-Grant, M. et al. Acetylation of histone H4 by Esa1 is required for DNA double-strand break repair. Nature 419, 411–415 (2002) doi:10.1038/nature01035

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