p73 suppresses polyploidy and aneuploidy in the absence of functional p53.
Previous studies showed that p53 plays a central role in G1 and DNA damage checkpoints, thus contributing to genomic stability. We show here that p73 also plays a role in genomic integrity but this mechanism is manifest only when p53 is lost. Isolated p73 loss in primary cells does not induce genomic instability. Instead, it results in impaired proliferation and premature senescence due to compensatory activation of p53. Combined loss of p73 and p53 rescues these defects, but at the expense of exacerbated genomic instability. This leads to rapid increase in polyploidy and aneuploidy, markedly exceeding that of p53 loss alone. Constitutive deregulation of cyclin-Cdk activities and excess failure of the G2/M DNA damage checkpoint appear to fuel increased ploidy abnormalities upon p53/p73 loss, while primary mitotic defects do not play a causal role. These data indicate that p73 is essential for suppressing polyploidy and aneuploidy when p53 is inactivated.
Talos
Flaminia
F
Department of Pathology, Health Science Center, State University of New York at Stony Brook, Stony Brook, NY 11794, USA.
Nemajerova
Alice
A
Flores
Elsa R
ER
Petrenko
Oleksi
O
Moll
Ute M
UM
D000782:Aneuploidy; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016195:G2 Phase; D042822:Genomic Instability / Q000235:genetics; D051379:Mice; D008938:Mitosis; D009687:Nuclear Proteins / Q000378:metabolism*; D011123:Polyploidy; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2