Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1.

TitleDual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1.
Publication TypeJournal Article
Year of Publication2012
AuthorsSingh, N, Basnet, H, Wiltshire, TD, Mohammad, DH, Thompson, JR, Héroux, A, Botuyan, MV, Yaffe, MB, Couch, FJ, Rosenfeld, MG, Mer, G
JournalProc Natl Acad Sci U S A
Volume109
Issue36
Pagination14381-6
Date Published2012 Sep 4
ISSN1091-6490
KeywordsCalorimetry, 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.

DOI10.1073/pnas.1212366109
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID22908299
PubMed Central IDPMC3437875
Grant ListCA097134 / 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