Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Genes and Development - Tập 22 Số 22 - Trang 3158-3171 - 2008
Sonam Mehrotra1, Shahina B. Maqbool2, Alexis Kolpakas2, Katherine Murnen3,2, Brian R. Calvi4,2
1Department of Biology, Syracuse University, Syracuse, New York 13244 USA
2Syracuse University
3Johns Hopkins University
4Indiana University, Bloomington

Tóm tắt

Initiation of DNA replication at origins more than once per cell cycle results in rereplication and has been implicated in cancer. Here we use Drosophila to examine the checkpoint responses to rereplication in a developmental context. We find that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage. In most cells, this rereplication triggers caspase activation and apoptotic cell death mediated by both p53-dependent and -independent pathways. Elevated Dup also caused DNA damage in endocycling cells, which switch to a G/S cycle during normal development, indicating that rereplication and the endocycling DNA reduplication program are distinct processes. Unexpectedly, however, endocycling cells do not apoptose regardless of tissue type. Our combined evidence suggests that endocycling apoptosis is repressed in part because proapoptotic gene promoters are silenced. Normal endocycling cells had DNA lesions near heterochromatin, which increased after rereplication, explaining why endocycling cells must constantly repress the genotoxic apoptotic response. Our results reveal a novel regulation of apoptosis in development and new insights into the little-understood endocycle. Similar mechanisms may operate during vertebrate development, with implications for cancer predisposition in certain tissues.

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Genes and Development

Tập 22 Số 22

3158-3171

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