The proline rich domain of p53 is dispensable for MGMT-dependent DNA repair and cell survival following alkylation damage
The proline rich domain of p53 is dispensable for MGMT-dependent DNA repair and cell survival following alkylation damage
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DOI：
10.1038/cdd.2017.116
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发表时间：
2017-11-01
影响因子：
12.4
通讯作者：
Green, Douglas R.
中科院分区：
文献类型：
--
作者：
Baran, Katherine;Yang, Mao;Green, Douglas R.
除了促进细胞死亡和衰老外，p53还具有重要的细胞存活功能。突变型p53，缺乏脯氨酸丰富的结构域（p53（Δ P）），这是缺乏控制细胞死亡和细胞周期停滞，被用来确定生物学手段p53介导的DNA损伤后的生存。虽然p53（Delta P）和p53（-/-）细胞对许多DNA损伤剂具有同等的抵抗力，但p53（Delta P）细胞对高剂量的烷基化剂Diazald（N-甲基-N-（对甲苯磺酰基））亚硝基胺）表现出极强的抵抗力，与完全缺乏p53功能的细胞相比。我们确定，p53（Δ P）能够转录修复基因，MGMT（O 6-甲基鸟嘌呤-DNA甲基转移酶）辐射或烷基化损伤后，导致DNA修复和细胞存活。与这些观察结果一致，相对于p53（-/-）小鼠，p53（Delta P）小鼠在IR后显示出增强的存活率。在p53（Δ P）细胞中抑制或缺失MGMT表达抑制DNA修复和烷基化损伤后的存活，而在p53缺陷细胞中MGMT过表达促进DNA修复并赋予存活优势。这项研究表明，当细胞死亡和细胞周期阻滞途径被抑制时，p53仍然可以介导MGMT依赖性修复，以促进DNA损伤后的细胞存活。
In addition to promoting cell death and senescence, p53 also has important cellular survival functions. A mutant p53, lacking a proline-rich domain (p53(Delta P)), that is deficient in controlling both cell death and cell cycle arrest, was employed to determine the biological means by which p53 mediates survival upon DNA damage. While p53(Delta P) and p53(-/-) cells were equally resistant to many DNA damaging agents, p53(Delta P) cells showed an exquisite resistance to high doses of the alkylating agent Diazald (N-Methyl-N-(p-tolylsulfonyl)nitrosamide), as compared to cells completely deficient for p53 function. We determined that p53(Delta P) was capable of transcribing the repair gene, MGMT (O6-methylguanine-DNA methyltransferase) after irradiation or alkylation damage, resulting in DNA repair and cell survival. Consistent with these observations, p53(Delta P) mice show enhanced survival after IR relative to p53(-/-) mice. Suppression or deletion of MGMT expression in p53(Delta P) cells inhibited DNA repair and survival after alkylation damage, whereas MGMT overexpression in p53-deficient cells facilitated DNA repair and conferred survival advantage. This study shows that when cell death and cell cycle arrest pathways are inhibited, p53 can still mediate MGMT-dependent repair, to promote cell survival upon DNA damage.