Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence.
The RB protein family (RB, p107, and p130) has overlapping and compensatory functions in cell-cycle control. However, cancer-associated mutations are almost exclusively found in RB, implying that RB has a nonredundant role in tumor suppression. We demonstrate that RB preferentially associates with E2F target genes involved in DNA replication and is uniquely required to repress these genes during senescence but not other growth states. Consequently, RB loss leads to inappropriate DNA synthesis following a senescence trigger and, together with disruption of a p21-mediated cell-cycle checkpoint, enables extensive proliferation and rampant genomic instability. Our results identify a nonredundant RB effector function that may contribute to tumor suppression and reveal how loss of RB and p53 cooperate to bypass senescence.
Chicas
Agustin
A
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Wang
Xiaowo
X
Zhang
Chaolin
C
McCurrach
Mila
M
Zhao
Zhen
Z
Mert
Ozlem
O
Dickins
Ross A
RA
Narita
Masashi
M
Zhang
Michael
M
Lowe
Scott W
SW
D016922:Cellular Senescence / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics; D018014:Gene Transfer Techniques; D016147:Genes, Tumor Suppressor; D005822:Genetic Vectors; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D012175:Retinoblastoma / Q000235:genetics / Q000473:pathology*; D016160:Retinoblastoma Protein / Q000172:deficiency / Q000235:genetics
D004273:DNA, Neoplasm; D016160:Retinoblastoma Protein
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