Histone Ubiquitination Associates with BRCA1-Dependent DNA Damage Response

Abstract

Histone ubiquitination participates in multiple cellular processes, including the DNA damage response. However, the molecular mechanisms involved are not clear. Here, we have identified that RAP80/UIMC1 (ubiquitin interaction motif containing 1), a functional partner of BRCA1, recognizes ubiquitinated histones H2A and H2B. The interaction between RAP80 and ubiquitinated histones H2A and H2B is increased following DNA damage. Since RAP80 facilitates BRCA1's translocation to DNA damage sites, our results indicate that ubiquitinated histones H2A and H2B could be upstream partners of the BRCA1/RAP80 complex in the DNA damage response. Moreover, we have found that RNF8 (ring finger protein 8), an E3 ubiquitin ligase, regulates ubiquitination of both histones H2A and H2B. In RNF8-deficient mouse embryo fibroblasts, ubiquitination of both histones H2A and H2B is dramatically reduced, which abolishes the DNA damage-induced BRCA1 and RAP80 accumulation at damage lesions on the chromatin. Taken together, our results suggest that ubiquitinated histones H2A and H2B may recruit the BRCA1 complex to DNA damage lesions on the chromatin.

SUPPLEMENTAL MATERIAL

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

ACKNOWLEDGMENTS

We thank members of the Ben Margolis lab for technical support. We thank Andre Nussenzweig for invaluable reagents.

This work was supported by the Department of Defense (grant BC050367 to X.Y.), the National Institutes of Health (grant CA132755 to X.Y.), the University of Michigan Cancer Center, and the GI Peptide Research Center of the University of Michigan. X.Y. is a recipient of an AACR-Susan G. Komen for the Cure Career Development Award for Breast Cancer Research. J.C. is a recipient of an Era of Hope Scholar award from the Department of Defense and is a member of the Mayo Clinic Breast SPORE program (grant P50 CA116201). J.C. was also supported by the National Cancer Institute (grants CA89239, CA92312, and CA100109). M.S.Y.H. is supported by an Anna Fuller Fund Fellowship.