MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage

Jamie L. Wood, Namit Singh, Georges Mer, Junjie Chen

Research output: Contribution to journalArticle

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Abstract

Microcephalin (MCPH1) is one of the causative genes for the autosomal recessive disorder, primary microcephaly, characterized by dramatic reduction in brain size and mental retardation. MCPH1also functions in the DNA damage response, participating in cell cycle checkpoint control. However, how MCPH1 is regulated in the DNA damage response still remains unknown. Here we report that the ability of MCPH1 to localize to the sites of DNA double-strand breaks depends on its C-terminal tandem BRCT domains. Although MCPH1 foci formation depends on H2AX phosphorylation after DNA damage, it can occur independently of MDC1. We also show that MCPH1 binds to a phospho-H2AX peptide in vitro with an affinity similar to that of MDC1, and overexpression of wild type, but not C-BRCT mutants of MCPH1, can interfere with the foci formation of MDC1 and 53BP1. Collectively, our data suggest MCPH1 is recruited to double-strand breaks via its interaction with γH2AX, which is mediated by MCPH1 C-terminal BRCT domains. These observations support that MCPH1 acts early in DNA damage responsive pathways.

Original languageEnglish (US)
Pages (from-to)35416-35423
Number of pages8
JournalJournal of Biological Chemistry
Volume282
Issue number48
DOIs
StatePublished - Nov 30 2007

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DNA Damage
DNA
Cell Cycle Checkpoints
Aptitude
Double-Stranded DNA Breaks
Phosphorylation
Intellectual Disability
Brain
Peptides
Genes
Cells

ASJC Scopus subject areas

  • Biochemistry

Cite this

MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. / Wood, Jamie L.; Singh, Namit; Mer, Georges; Chen, Junjie.

In: Journal of Biological Chemistry, Vol. 282, No. 48, 30.11.2007, p. 35416-35423.

Research output: Contribution to journalArticle

Wood, Jamie L. ; Singh, Namit ; Mer, Georges ; Chen, Junjie. / MCPH1 functions in an H2AX-dependent but MDC1-independent pathway in response to DNA damage. In: Journal of Biological Chemistry. 2007 ; Vol. 282, No. 48. pp. 35416-35423.
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