Replicative senescence is ATM driven, reversible, and accelerated by hyperactivation of ATM at normoxia.

ABSTRACT: Programmed telomere shortening limits tumorigenesis through the induction of replicative senescence. Here we address three long-standing questions concerning senescence. First, we show that the ATM kinase is solely responsible for the induction of replicative senescence. Senescence was delayed by ATM inhibition (ATMi) or overexpression of TRF2, the shelterin subunit dedicated to ATM repression. In contrast, there was no evidence for ATR signaling contributing to replicative senescence even when ATMi was combined with ATR inhibition. Second, we show ATMi can induce apparently normal cell divisions in a subset of senescent cells, indicating that senescence can be reversed. Third, we show that the extended replicative life span at low (physiological) oxygen is due to diminished ATM activity.

SUBMITTER: Stuart A 

PROVIDER: S-EPMC11230194 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature