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

  1. Sonam Mehrotra1,
  2. Shahina B. Maqbool,
  3. Alexis Kolpakas,
  4. Katherine Murnen2, and
  5. Brian R. Calvi3,4
  1. Department of Biology, Syracuse University, Syracuse, New York 13244, USA

Abstract

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.

Keywords

Footnotes

  • 1 Present addresses:

    1 Department of Radiation Cancer Biology, Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, 195 Little Albany St., New Brunswick, NJ 08903, USA;

  • 2 Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, 515 PCTB, 725 N. Wolfe St., Baltimore, MD 21205, USA;

  • 3 Department of Biology, Indiana University, 1001 East 3rd St., Bloomington, IN 47405, USA.

  • 4 Corresponding author.

    4 E-MAIL bcalvi{at}indiana.edu; FAX (812) 855-6705.

  • Supplemental material is available at http://www.genesdev.org.

  • Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1710208.

    • Received June 26, 2008.
    • Accepted September 22, 2008.
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