Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality

David W. Koh, Ann M Lawler, Marc F. Poitras, Masayuki Sasaki, Sigrid Wattler, Michael C. Nehls, Tobias Stöger, Guy G. Poirier, Valina Dawson, Ted M Dawson

Research output: Contribution to journalArticle

Abstract

The metabolism of poly(ADP-ribose) (PAR) is critical for genomic stability in multicellular eukaryotes. Here, we show that the failure to degrade PAR by means of disruption of the murine poly(ADP-ribose) glycohydrolase (PARG) gene unexpectedly causes early embryonic lethality and enhanced sensitivity to genotoxic stress. This lethality results from the failure to hydrolyze PAR, because PARG null embryonic day (E) 3.5 blastocysts accumulate PAR and concurrently undergo apoptosis. Moreover, embryonic trophoblast stem cell lines established from early PARG null embryos are viable only when cultured in medium containing the poly(ADP-ribose) polymerase inhibitor benzamide. Cells lacking PARG also show reduced growth, accumulation of PAR, and increased sensitivity to cytotoxicity induced by N-methyl-N′-nitro-N-nitrosoguanidine and menadione after benzamide withdrawal. These results provide compelling evidence that the failure to degrade PAR has deleterious consequences. Further, they define a role for PARG in embryonic development and a protective role in the response to genotoxic stress.

Original languageEnglish (US)
Pages (from-to)17699-17704
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number51
DOIs
StatePublished - Dec 21 2004

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Poly Adenosine Diphosphate Ribose
DNA Damage
Vitamin K 3
Methylnitronitrosoguanidine
Genomic Instability
Trophoblasts
Blastocyst
Embryonic Stem Cells
Eukaryota
Embryonic Development
Embryonic Structures
poly ADP-ribose glycohydrolase
Apoptosis
Cell Line
Growth
Genes

Keywords

  • Apoptosis
  • Poly(ADP-ribose) glycohydrolase
  • Poly(ADP-ribose) polymerase

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality. / Koh, David W.; Lawler, Ann M; Poitras, Marc F.; Sasaki, Masayuki; Wattler, Sigrid; Nehls, Michael C.; Stöger, Tobias; Poirier, Guy G.; Dawson, Valina; Dawson, Ted M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 51, 21.12.2004, p. 17699-17704.

Research output: Contribution to journalArticle

Koh, David W. ; Lawler, Ann M ; Poitras, Marc F. ; Sasaki, Masayuki ; Wattler, Sigrid ; Nehls, Michael C. ; Stöger, Tobias ; Poirier, Guy G. ; Dawson, Valina ; Dawson, Ted M. / Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 51. pp. 17699-17704.
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