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

Proc Natl Acad Sci U S A. 2012 Sep 4;109(36):14381-6. doi: 10.1073/pnas.1212366109. Epub 2012 Aug 20.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Calorimetry
  • Cell Cycle Proteins
  • Cloning, Molecular
  • Crystallography, X-Ray
  • Cytoskeletal Proteins
  • DNA Damage / physiology
  • DNA Repair / physiology*
  • Escherichia coli
  • Genetic Vectors / genetics
  • Histones / metabolism*
  • Humans
  • Microscopy, Fluorescence
  • Models, Molecular*
  • Nerve Tissue Proteins / chemistry*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Phosphoserine / metabolism*
  • Phosphotyrosine / metabolism*

Substances

  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • Histones
  • MCPH1 protein, human
  • Nerve Tissue Proteins
  • Phosphoserine
  • Phosphotyrosine

Associated data

  • PDB/3SZM
  • PDB/3U3Z