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

Article metrics


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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1

    Vettese-Dadey, M. et al. Acetylation of histone H4 plays a primary role in enhancing transcription factor binding to nucleosomal DNA in vitro. EMBO J. 15, 2508–2518 (1996)

  2. 2

    Lee, D. Y., Hayes, J. J., Pruss, D. & Wolffe, A. P. A positive role for histone acetylation in transcription factor access to nucleosomal DNA. Cell 72, 73–84 (1993)

  3. 3

    Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996)

  4. 4

    Braunstein, M., Sobel, R. E., Allis, C. D., Turner, B. M. & Broach, J. R. Efficient transcriptional silencing in Saccharomyces cerevisiae requires a heterochromatin histone acetylation pattern. Mol. Cell. Biol. 16, 4349–4356 (1996)

  5. 5

    Allfrey, V. G., Pogo, B. G., Littau, V. C., Gershey, E. L. & Mirsky, A. E. Histone acetylation in insect chromosomes. Science 159, 314–316 (1968)

  6. 6

    Strahl, B. D. & Allis, C. D. The language of covalent histone modifications. Nature 403, 41–45 (2000)

  7. 7

    Barlev, N. A. et al. Repression of GCN5 histone acetyltransferase activity via bromodomain-mediated binding and phosphorylation by the Ku-DNA-dependent protein kinase complex. Mol. Cell. Biol. 18, 1349–1358 (1998)

  8. 8

    Iizuka, M. & Stillman, B. Histone acetyltransferase HBO1 interacts with the ORC1 subunit of the human initiator protein. J. Biol. Chem. 274, 23027–23034 (1999)

  9. 9

    Burke, T. W., Cook, J. G., Asano, M. & Nevins, J. R. Replication factors MCM2 and ORC1 interact with the histone acetyltransferase HBO1. J. Biol. Chem. 276, 15397–15408 (2001)

  10. 10

    Megee, P. C., Morgan, B. A., Mittman, B. A. & Smith, M. M. Genetic analysis of histone H4: essential role of lysines subject to reversible acetylation. Science 247, 841–845 (1990)

  11. 11

    Megee, P. C., Morgan, B. A. & Smith, M. M. Histone H4 and the maintenance of genome integrity. Genes Dev. 9, 1716–1727 (1995)

  12. 12

    Clarke, A. S., Lowell, J. E., Jacobson, S. J. & Pillus, L. Esa1p is an essential histone acetyltransferase required for cell cycle progression. Mol. Cell. Biol. 19, 2515–2526 (1999)

  13. 13

    Reid, J. L., Iyer, V. R., Brown, P. O. & Struhl, K. Coordinate regulation of yeast ribosomal protein genes is associated with targeted recruitment of Esa1 histone acetylase. Mol. Cell 6, 1297–1307 (2000)

  14. 14

    Ikura, T. et al. Involvement of the TIP60 histone acetylase complex in DNA repair and apoptosis. Cell 102, 463–473 (2000)

  15. 15

    Boulton, S. J. & Jackson, S. P. Saccharomyces cerevisiae Ku70 potentiates illegitimate DNA double-strand break repair and serves as a barrier to error-prone DNA repair pathways. EMBO J. 15, 5093–5103 (1996)

  16. 16

    Tsukamoto, Y., Kato, J. & Ikeda, H. Silencing factors participate in DNA repair and recombination in Saccharomyces cerevisiae. Nature 388, 900–903 (1997)

  17. 17

    Wilson, T. E. & Lieber, M. R. Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase β (Pol4)-dependent pathway. J. Biol. Chem. 274, 23599–23609 (1999)

  18. 18

    D'Arpa, P., Beardmore, C. & Liu, L. F. Involvement of nucleic acid synthesis in cell killing mechanisms of topoisomerase poisons. Cancer Res. 50, 6919–6924 (1990)

  19. 19

    Harata, M. et al. The nuclear actin-related protein of Saccharomyces cerevisiae, Act3p/Arp4, interacts with core histones. Mol. Biol. Cell 10, 2595–2605 (1999)

  20. 20

    Galarneau, L. et al. Multiple links between the NuA4 histone acetyltransferase complex and epigenetic control of transcription. Mol. Cell 5, 927–937 (2000)

  21. 21

    Martin, S. G., Laroche, T., Suka, N., Grunstein, M. & Gasser, S. M. Relocalization of telomeric Ku and SIR proteins in response to DNA strand breaks in yeast. Cell 97, 621–633 (1999)

  22. 22

    Vignali, M., Steger, D. J., Neely, K. E. & Workman, J. L. Distribution of acetylated histones resulting from Gal4–VP16 recruitment of SAGA and NuA4 complexes. EMBO J. 19, 2629–2640 (2000)

  23. 23

    Kowalczykowski, S. C. Initiation of genetic recombination and recombination-dependent replication. Trends Biochem. Sci. 25, 156–165 (2000)

  24. 24

    Downs, J. A., Lowndes, N. F. & Jackson, S. P. A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature 408, 1001–1004 (2000)

  25. 25

    Grant, P. A. et al. Yeast Gcn5 functions in two multisubunit complexes to acetylate nucleosomal histones: characterization of an Ada complex and the SAGA (Spt/Ada) complex. Genes Dev. 11, 1640–1650 (1997)

  26. 26

    Lin, Y. S., Carey, M. F., Ptashne, M. & Green, M. R. GAL4 derivatives function alone and synergistically with mammalian activators in vitro. Cell 54, 659–664 (1988)

  27. 27

    Owen-Hughes, T. et al. Analysis of nucleosome disruption by ATP-driven chromatin remodeling complexes. Methods Mol. Biol. 119, 319–331 (1999)

Download references


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.

Author information

Correspondence to Michael F. Christman.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.