title: Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability.
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, gamma-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 (m53BP1(tr/tr)), we have created an animal model to further explore its biochemical and genetic roles in vivo. We find that m53BP1(tr/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 m53BP1(tr/tr) mice are sensitive to ionizing radiation (gamma-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Health Sciences Center, Houston, Texas 77030, USA.
authors.forename: Julio C
authors.initials: JC
authors.lastname: Morales
authors.forename: Zhenfang
authors.initials: Z
authors.lastname: Xia
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Melissa B
authors.initials: MB
authors.lastname: Aldrich
authors.forename: Bin
authors.initials: B
authors.lastname: Wang
authors.forename: Corina
authors.initials: C
authors.lastname: Rosales
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Walter N
authors.initials: WN
authors.lastname: Hittelman
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.forename: Phillip B
authors.initials: PB
authors.lastname: Carpenter
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics; D019313:BRCA1 Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002868:Chromosomal Proteins, Non-Histone; D002869:Chromosome Aberrations / Q000528:radiation effects*; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D016678:Genome; D006128:Growth / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins; D020079:Terminal Repeat Sequences; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1