Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse
Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse
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DOI：
10.1093/emboj/cdg206
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发表时间：
2003-05-01
期刊：
影响因子：
11.4
通讯作者：
de Murcia, G
中科院分区：
文献类型：
--
作者：
de Murcia, JMN;Ricoul, M;de Murcia, G
DNA 损伤依赖性聚（ADP-核糖）聚合酶 PARP-1 和 PARP-2 可形成同二聚体和异二聚体，并且均参与碱基切除修复 (BER) 途径。在此，我们报告携带 PARP-2 基因靶向破坏的小鼠对电离辐射敏感。烷化剂处理后，parp-2(-/-) 衍生的小鼠胚胎成纤维细胞表现出复制后基因组不稳定性增加、G(2)/M 积累和伴随动粒缺陷的染色体错误分离。此外，parp-1(-/-)parp-2(-/-)双突变小鼠无法存活并在原肠胚形成时死亡，这表明PARP-1和PARP-2和/或DNA依赖性聚(ADP-核糖基)的表达在早期胚胎发生过程中是必需的。有趣的是，在 E9.5 的 parp-1(+/-)parp-2(-/-) 突变体中观察到特定的雌性胚胎致死率。 E8.5 胚胎成纤维细胞的元期分析强调了女性 X 染色体的特定不稳定性，但男性则不然。总之，这些结果支持了这样的观点：PARP-1 和 PARP-2 在维持基因组稳定性方面具有重叠和非冗余的功能。
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.