A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency.
The molecular pathways leading from genomic instability to cellular senescence and/or cell death remain incompletely characterized. Using mouse embryonic fibroblasts with constitutively increased DNA damage due to the absence of the full-length form of the tumor suppressor Brca1 (Brca1(Delta 11/Delta 11)), we show that deletion of p53 binding protein 1 (53BP1) selectivity abrogates senescence and cell death stimulated by reduced Brca1 activity. Furthermore, the embryonic lethality induced by Brca1 mutation can be alleviated by 53BP1 deletion. Adult Brca1(Delta 11/Delta 11)53BP1(-/-) manifest constitutively high levels of genomic instability, yet age relatively normally, with a surprisingly low incidence of overall tumor formation. Together, these in vitro and in vivo data suggest that 53BP1 is specifically required for the development of premature senescence and apoptosis induced by Brca1 deficiency. These observations may have important implications for Brca1-mediated tumor formation as well as for the molecular pathway leading from genomic instability to organismal aging.
Cao
Liu
L
Translational Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA. liu.cao@nih.gov
Xu
Xioaling
X
Bunting
Samuel F
SF
Liu
Jie
J
Wang
Rui-Hong
RH
Cao
Longyue L
LL
Wu
J Julie
JJ
Peng
Tie-Nan
TN
Chen
Junjie
J
Nussenzweig
Andre
A
Deng
Chu-Xia
CX
Finkel
Toren
T
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein / Q000172:deficiency* / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics* / Q000528:radiation effects; D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000633:toxicity; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005720:Gamma Rays; D042822:Genomic Instability / Q000187:drug effects / Q000528:radiation effects; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
D064007:Ataxia Telangiectasia Mutated Proteins; D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004317:Doxorubicin; D006657:Histones; D006861:Hydrogen Peroxide; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D000071857:Tumor Suppressor p53-Binding Protein 1; C498302:Trp53bp1 protein, mouse; C576325:Atm protein, mouse; C578633:Chek2 protein, mouse; C475961:gamma-H2AX protein, mouse