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Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen

ABSTRACT: Replicative senescence, a powerful tumor suppressor pathway, occurs when a few critically-short telomeres activate the DNA damage response (DDR). We show that ATM is the sole DDR kinase responsible for the induction and maintenance of replicative senescence and that ATM inhibition can induce normal cell divisions in senescent cells. Compared to non-physiological atmospheric (~20%) oxygen, cells grown at physiological (3%) oxygen were more tolerant to critically-short telomeres, explaining their extended replicative lifespan. We show that this tolerance is due to attenuation of the ATM response to double-strand breaks (DSBs) and unprotected telomeres. Our data indicate that the reduced ATM response to DSBs at 3% oxygen is due to increased ROS, which induces disulfide-bridges in ATM, generating crosslinked ATM dimers that do not respond to DSBs. This regulation of cellular lifespan through attenuation of ATM at physiological oxygen has implications for tumor suppression through telomere shortening.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

SUBMITTER: Henry Sanford

LAB HEAD: Ekaterina V.Vinogradova

PROVIDER: PXD069897 | Pride | 2026-02-12

REPOSITORIES: Pride

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Attenuation of ATM signaling by ROS delays replicative senescence at physiological oxygen.

Stuart Alexander J AJ Takai Kaori K KK Gabbasova Railia R RR Sanford Henry H Vinogradova Ekaterina V EV de Lange Titia T

Molecular cell 20251201 24

Replicative senescence is a powerful tumor suppressor pathway that curbs proliferation of human cells when a few critically-short telomeres activate the DNA damage response (DDR). We show that ATM is the sole DDR kinase responsible for the induction and maintenance of replicative senescence and that ATM inhibition can induce normal cell divisions in senescent cells. Compared to non-physiological atmospheric (∼20%) oxygen, primary fibroblast cells grown at physiological (3%) oxygen were more tole ...[more]

PMID: 41330385

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Project description:Aberrant cell proliferation, a hallmark of most cancers, requires the escape from intrinsic antitumour barriers. Primary among these is the DNA damage response (DDR). In both cell culture-models and in early stages of tumorigenesis in vivo, activated oncogenes induce DNA replication stress and DNA double-strand breaks (DSBs), leading to DDR activation and p53-dependent apoptosis and/or senescence. The means by which tumour initiating cells, also termed cancer stem cells (CSCs), circumvent this oncosuppressive response is unknown. Here we demonstrate that the ZEB1 transcription factor provides breast CSCs with the ability to withstand an aberrant mitogenic activity. Its forced expression in human mammary epithelial cells is sufficient to alleviate DNA replicative stress and to decrease the production of reactive oxygen species, an important contributor to DDR and oncogene-induced senescence. Consistently, human breast cancer cells with endogenous ZEB1 expression show two characteristic features: low levels of DSBs and DDR markers, reflecting mitigation of the DNA replication stress, and a low p53 mutation frequency, reflecting a weak selective pressure for inactivation. Using high-throughput sequencing analysis of controlled cellular models, we further demonstrate that ZEB1 delays the onset of structural chromosomal instability (CIN), a known consequence of replicative stress and prevents the emergence of chromosome 8p deletions and 8q amplifications, two prevalent abnormalities in high grade breast cancers. Supporting these findings, ZEB1 expression discriminates human breast tumours by their copy number alterations (CNAs) and chromosome 8 aberrations. We propose that the tumorigenic potential of CSCs relies upon their unique capacity to tolerate oncogenic stimuli through the alleviation of DNA replication stress. Immortalized human mammary epithelial cells were infected with retrovirus expressing H-RASV12 with or without a retrovirus expressing ZEB1.

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