Histone ubiquitination associates with BRCA1-dependent DNA damage response.
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.
Wu
Jiaxue
J
Department of Internal Medicine, Division of Molecular Medicine and Genetics, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
Huen
Michael S Y
MS
Lu
Lin-Yu
LY
Ye
Lin
L
Dou
Yali
Y
Ljungman
Mats
M
Chen
Junjie
J
Yu
Xiaochun
X
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins; D006367:HeLa Cells; D056488:Histone Chaperones; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
D019313:BRCA1 Protein; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D056488:Histone Chaperones; D006657:Histones; D009687:Nuclear Proteins; C466234:UIMC1 protein, human; D025801:Ubiquitin