Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse

EMBO J. 2003 May 1;22(9):2255-63. doi: 10.1093/emboj/cdg206.

Abstract

The DNA damage-dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, homo- and heterodimerize and are both involved in the base excision repair (BER) pathway. Here, we report that mice carrying a targeted disruption of the PARP-2 gene are sensitive to ionizing radiation. Following alkylating agent treatment, parp-2(-/-)-derived mouse embryonic fibroblasts exhibit increased post-replicative genomic instability, G(2)/M accumulation and chromosome mis-segregation accompanying kinetochore defects. Moreover, parp-1(-/-)parp-2(-/-) double mutant mice are not viable and die at the onset of gastrulation, demonstrating that the expression of both PARP-1 and PARP-2 and/or DNA-dependent poly(ADP-ribosyl) ation is essential during early embryogenesis. Interestingly, specific female embryonic lethality is observed in parp-1(+/-)parp-2(-/-) mutants at E9.5. Meta phase analyses of E8.5 embryonic fibroblasts highlight a specific instability of the X chromosome in those females, but not in males. Together, these results support the notion that PARP-1 and PARP-2 possess both overlapping and non-redundant functions in the maintenance of genomic stability.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics*
  • Base Sequence
  • Chromosomes*
  • DNA Damage
  • DNA Primers
  • Embryonic and Fetal Development / physiology*
  • Genes, Lethal
  • Isoenzymes / genetics
  • Isoenzymes / physiology*
  • Methylnitrosourea / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Molecular Sequence Data
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / physiology*
  • Radiation Tolerance

Substances

  • DNA Primers
  • Isoenzymes
  • Methylnitrosourea
  • Poly(ADP-ribose) Polymerases