Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability

Julio C. Morales, Zhenfang Xia, Tao Lu, Melissa B. Aldrich, Bin Wang, Corina Rosales, Rodney E. Kellems, Walter N. Hittelman, Stephen J. Elledge, Phillip B. Carpenter

Research output: Contribution to journalArticle

113 Scopus citations

Abstract

p53-binding protein-1 (53BP1) is phosphorylated in response to DNA damage and rapidly relocalizes to presumptive sites of DNA damage along with Mre11 and the phosphorylated histone 2A variant, γ-H2AX. 53BP1 associates with the BRCA1 tumor suppressor, and knock-down experiments with small interfering RNA have revealed a role for the protein in the checkpoint response to DNA damage. By generating mice defective in m53BP1 (m53BP1tr/tr), we have created an animal model to further explore its biochemical and genetic roles in vivo. We find that m53BP1tr/tr animals are growth-retarded and show various immune deficiencies including a specific reduction in thymus size and T cell count. Consistent with a role in responding to DNA damage, we find that m53BP1tr/tr mice are sensitive to ionizing radiation (γ-IR), and cells from these animals exhibit chromosomal abnormalities consistent with defects in DNA repair. Thus, 53BP1 is a critical element in the DNA damage response and plays an integral role in maintaining genomic stability.

Original languageEnglish (US)
Pages (from-to)14971-14977
Number of pages7
JournalJournal of Biological Chemistry
Volume278
Issue number17
DOIs
StatePublished - Apr 25 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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