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

Sonam Mehrotra, Shahina B. Maqbool, Alexis Kolpakas, Katherine Murnen, Brian R. Calvi

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3158-3171
Number of pages14
JournalGenes and Development
Volume22
Issue number22
DOIs
StatePublished - Nov 15 2008
Externally publishedYes

Fingerprint

DNA Damage
DNA
Drosophila
Apoptosis
Replication Origin
Heterochromatin
Caspases
DNA Replication
Vertebrates
Neoplasms
Cell Cycle
Cell Death
Genes

Keywords

  • Apoptosis
  • Checkpoint
  • DNA damage
  • DNA replication
  • Endocycle

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress. / Mehrotra, Sonam; Maqbool, Shahina B.; Kolpakas, Alexis; Murnen, Katherine; Calvi, Brian R.

In: Genes and Development, Vol. 22, No. 22, 15.11.2008, p. 3158-3171.

Research output: Contribution to journalArticle

Mehrotra, Sonam ; Maqbool, Shahina B. ; Kolpakas, Alexis ; Murnen, Katherine ; Calvi, Brian R. / Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress. In: Genes and Development. 2008 ; Vol. 22, No. 22. pp. 3158-3171.
@article{6ac239256a6b4ceea1e6d4c856ff5f88,
title = "Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress",
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 = "Apoptosis, Checkpoint, DNA damage, DNA replication, Endocycle",
author = "Sonam Mehrotra and Maqbool, {Shahina B.} and Alexis Kolpakas and Katherine Murnen and Calvi, {Brian R.}",
year = "2008",
month = "11",
day = "15",
doi = "10.1101/gad.1710208",
language = "English (US)",
volume = "22",
pages = "3158--3171",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "22",

}

TY - JOUR

T1 - Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

AU - Mehrotra, Sonam

AU - Maqbool, Shahina B.

AU - Kolpakas, Alexis

AU - Murnen, Katherine

AU - Calvi, Brian R.

PY - 2008/11/15

Y1 - 2008/11/15

N2 - 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.

AB - 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.

KW - Apoptosis

KW - Checkpoint

KW - DNA damage

KW - DNA replication

KW - Endocycle

UR - http://www.scopus.com/inward/record.url?scp=56549098376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=56549098376&partnerID=8YFLogxK

U2 - 10.1101/gad.1710208

DO - 10.1101/gad.1710208

M3 - Article

VL - 22

SP - 3158

EP - 3171

JO - Genes and Development

JF - Genes and Development

SN - 0890-9369

IS - 22

ER -