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Early embryonic lethality in PARP-1 Atm double-mutant mice suggests a functional synergy in cell proliferation during

J Ménisser-de Murcia1, M Mark, O Wendling

  • 1Ecole Supérieure de Biotechnologie de Strasbourg, UPR 9003 du CNRS, Cancérogenèse et Mutagenèse Moléculaire et Structurale, 67400 Illkirch Cedex, France. josiane@esbs.u-strasbg.fr

Molecular and Cellular Biology
|March 10, 2001
PubMed

Insights

Poly (ADP-ribose) polymerase 1 (PARP-1) and ATM proteins work together to repair DNA damage, crucial for embryonic development. Double mutations lead to early embryonic death, highlighting their synergistic roles in DNA repair and survival.

Area of Science:

  • Molecular Biology
  • Genetics
  • Developmental Biology

Background:

  • Poly (ADP-ribose) polymerase 1 (PARP-1) and ATM are key proteins in DNA damage response pathways.
  • PARP-1 functions in base excision repair, while ATM regulates cell cycle checkpoints after double-strand breaks.
  • Mice lacking either PARP-1 or ATM exhibit radiosensitivity and chromosomal instability.

Purpose of the Study:

  • To investigate the functional synergy between PARP-1 and ATM in DNA damage response during embryogenesis.
  • To determine the embryonic lethality and tissue-specific effects of combined PARP-1 and ATM deficiencies.

Main Methods:

  • Generation of double mutant mice lacking both PARP-1 and Atm genes.
  • Observation of embryonic development and tissue morphology up to embryonic day 10.5.
  • Assessment of apoptosis in embryonic and extraembryonic tissues.

Main Results:

  • Double mutant embryos undergo apoptosis in embryonic tissues but not extraembryonic tissues.
  • Mutant embryos exhibit embryonic lethality by embryonic day 8.0.
  • Extraembryonic tissues appear normal until embryonic day 10.5, indicating tissue-specific sensitivity.

Conclusions:

  • PARP-1 and ATM exhibit functional synergy during embryogenesis, particularly when cell cycle checkpoints are inactive.
  • The combined deficiency of PARP-1 and ATM leads to severe developmental defects and embryonic lethality.
  • These findings suggest that PARP-1 and ATM play critical, cooperative roles in signaling DNA damage and/or distinct DNA repair pathways essential for early embryonic survival.

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