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DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells.

ABSTRACT: Recent studies have highlighted an apparently paradoxical link between self-renewal and senescence triggered by DNA damage in certain cell types. In addition, the finding that TP53 can suppress senescence has caused a re-evaluation of its functional role in regulating these outcomes. To investigate these phenomena and their relationship to pluripotency and senescence, we examined the response of the TP53-competent embryonal carcinoma (EC) cell line PA-1 to etoposide-induced DNA damage. Nuclear POU5F1/OCT4A and P21CIP1 were upregulated in the same cells following etoposide-induced G 2M arrest. However, while accumulating in the karyosol, the amount of OCT4A was reduced in the chromatin fraction. Phosphorylated CHK2 and RAD51/?H2AX-positive nuclear foci, overexpression of AURORA B kinase and moderate macroautophagy were evident. Upon release from G 2M arrest, cells with repaired DNA entered mitoses, while the cells with persisting DNA damage remained at this checkpoint or underwent mitotic slippage and gradually senesced. Reduction of TP53 using sh- or si-RNA prevented the upregulation of OCT4A and P21CIP1 and increased DNA damage. Subsequently, mitoses, micronucleation and senescence were all enhanced after TP53 reduction with senescence confirmed by upregulation of CDKN2A/P16INK4A and increased sa-?-galactosidase positivity. Those mitoses enhanced by TP53 silencing were shown to be multicentrosomal and multi-polar, containing fragmented and highly deranged chromosomes, indicating a loss of genome integrity. Together, these data suggest that TP53-dependent coupling of self-renewal and senescence pathways through the DNA damage checkpoint provides a mechanism for how embryonal stem cell-like EC cells safeguard DNA integrity, genome stability and ultimately the fidelity of self-renewal.

SUBMITTER: Jackson TR

PROVIDER: S-EPMC3587444 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells.

Jackson Thomas R TR Salmina Kristine K Huna Anda A Inashkina Inna I Jankevics Eriks E Riekstina Una U Kalnina Zane Z Ivanov Andrey A Townsend Paul A PA Cragg Mark S MS Erenpreisa Jekaterina J

Cell cycle (Georgetown, Tex.) 20120201 3

Recent studies have highlighted an apparently paradoxical link between self-renewal and senescence triggered by DNA damage in certain cell types. In addition, the finding that TP53 can suppress senescence has caused a re-evaluation of its functional role in regulating these outcomes. To investigate these phenomena and their relationship to pluripotency and senescence, we examined the response of the TP53-competent embryonal carcinoma (EC) cell line PA-1 to etoposide-induced DNA damage. Nuclear P ...[more]

PMID: 23287532

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Dataset Information

DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells.

Publications

DNA damage causes TP53-dependent coupling of self-renewal and senescence pathways in embryonal carcinoma cells.

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