Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality
Failure to degrade poly(ADP-ribose) causes increased sensitivity to cytotoxicity and early embryonic lethality
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DOI：
10.1073/pnas.0406182101
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发表时间：
2004-12-21
影响因子：
11.1
通讯作者：
Dawson, TM
中科院分区：
文献类型：
--
作者：
Koh, DW;Lawler, AM;Dawson, TM
在多细胞真核生物中，聚腺苷二磷酸核糖(PAR)的代谢对基因组的稳定性至关重要。在这里，我们表明，未能通过破坏小鼠多聚(ADPribose)糖水解酶(PARG)基因来降解PAR会意外地导致早期胚胎死亡和对遗传毒性应激的敏感性增强。这种致死性是由于PARG基因缺失的胚胎期(E)3.5天的囊胚积累了PAR并同时发生了细胞凋亡而导致的PAR不能被降解。此外，从早期PARG缺失胚胎建立的胚胎滋养层干细胞系只有在含有聚(ADPribose)聚合酶抑制剂苯甲酰胺的培养液中培养时才能存活。缺乏PARG的细胞在停用苯甲酰胺后也表现出生长减少、PAR积聚以及对N-甲基-N‘-硝基-N-亚硝基-N-亚硝胺和甲萘二酮诱导的细胞毒性的敏感性增加。这些结果提供了令人信服的证据，证明未能降低PAR具有有害的后果。此外，它们定义了PARG在胚胎发育中的作用以及在对遗传毒性应激的反应中的保护作用。
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(ADPribose) 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(ADPribose) 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.