Dissecting the Unique Role of the Retinoblastoma Tumor Suppressor during Cellular Senescence

Agustin Chicas, Xiaowo Wang, Chaolin Zhang, Mila McCurrach, Zhen Zhao, Ozlem Mert, Ross Alexander Dickins, Masashi Narita, Michael Qiwei Zhang, Scott W Lowe

Research output: Contribution to journalArticleResearchpeer-review

232 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)376 - 387
Number of pages12
JournalCancer Cell
Volume17
DOIs
Publication statusPublished - 2010
Externally publishedYes

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