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From Proteopedia
STRUCTURE OF HUMAN MICROCEPHALIN (MCPH1) TANDEM BRCT DOMAINS IN COMPLEX WITH A GAMMA-H2AX PHOSPHOPEPTIDE
Structural highlights
DiseaseMCPH1_HUMAN Premature chromosome condensation with microcephaly and intellectual deficit;Autosomal recessive primary microcephaly. Defects in MCPH1 are the cause of microcephaly primary type 1 (MCPH1) [MIM:251200; also known as true microcephaly or microcephaly vera. Microcephaly is defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits. This entity is inherited as autosomal recessive trait.[1] [2] [3] FunctionMCPH1_HUMAN Implicated in chromosome condensation and DNA damage induced cellular responses. May play a role in neurogenesis and regulation of the size of the cerebral cortex.[4] [5] [6] Publication Abstract from PubMedTyr142, 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. Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1.,Singh N, Basnet H, Wiltshire TD, Mohammad DH, Thompson JR, Heroux A, Botuyan MV, Yaffe MB, Couch FJ, Rosenfeld MG, Mer G Proc Natl Acad Sci U S A. 2012 Aug 20. PMID:22908299[7] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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