Title | Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Singh, N, Basnet, H, Wiltshire, TD, Mohammad, DH, Thompson, JR, Héroux, A, Botuyan, MV, Yaffe, MB, Couch, FJ, Rosenfeld, MG, Mer, G |
Journal | Proc Natl Acad Sci U S A |
Volume | 109 |
Issue | 36 |
Pagination | 14381-6 |
Date Published | 2012 Sep 4 |
ISSN | 1091-6490 |
Keywords | Calorimetry, Cloning, Molecular, Crystallography, X-Ray, DNA Damage, DNA Repair, Escherichia coli, Genetic Vectors, Histones, Humans, Microscopy, Fluorescence, Models, Molecular, Nerve Tissue Proteins, Phosphoserine, Phosphotyrosine |
Abstract | Tyr142, the C-terminal amino acid of histone variant H2A.X is phosphorylated by WSTF (Williams-Beuren syndrome transcription factor), a component of the WICH complex (WSTF-ISWI chromatin-remodeling complex), under basal conditions in the cell. In response to DNA double-strand breaks (DSBs), H2A.X is instantaneously phosphorylated at Ser139 by the kinases ATM and ATR and is progressively dephosphorylated at Tyr142 by the Eya1 and Eya3 tyrosine phosphatases, resulting in a temporal switch from a postulated diphosphorylated (pSer139, pTyr142) to monophosphorylated (pSer139) H2A.X state. How mediator proteins interpret these two signals remains a question of fundamental interest. We provide structural, biochemical, and cellular evidence that Microcephalin (MCPH1), an early DNA damage response protein, can read both modifications via its tandem BRCA1 C-terminal (BRCT) domains, thereby emerging as a versatile sensor of H2A.X phosphorylation marks. We show that MCPH1 recruitment to sites of DNA damage is linked to both states of H2A.X. |
DOI | 10.1073/pnas.1212366109 |
Alternate Journal | Proc. Natl. Acad. Sci. U.S.A. |
PubMed ID | 22908299 |
PubMed Central ID | PMC3437875 |
Grant List | CA097134 / CA / NCI NIH HHS / United States CA112967 / CA / NCI NIH HHS / United States CA132878 / CA / NCI NIH HHS / United States DK018477 / DK / NIDDK NIH HHS / United States DK39949 / DK / NIDDK NIH HHS / United States ES015339 / ES / NIEHS NIH HHS / United States NS034934 / NS / NINDS NIH HHS / United States R01 CA132878 / CA / NCI NIH HHS / United States R01 HL065445 / HL / NHLBI NIH HHS / United States R37 DK039949 / DK / NIDDK NIH HHS / United States / / Howard Hughes Medical Institute / United States |