Role for the BRCA1 C-terminal repeats (BRCT) protein 53BP1 in maintaining genomic stability.
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.
Morales
Julio C
JC
Department of Biochemistry and Molecular Biology, University of Texas Health Sciences Center, Houston, Texas 77030, USA.
Xia
Zhenfang
Z
Lu
Tao
T
Aldrich
Melissa B
MB
Wang
Bin
B
Rosales
Corina
C
Kellems
Rodney E
RE
Hittelman
Walter N
WN
Elledge
Stephen J
SJ
Carpenter
Phillip B
PB
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
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