Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1
Aag DNA Glycosylase Promotes Alkylation-Induced Tissue Damage Mediated by Parp1
复制标题
DOI：
10.1371/journal.pgen.1003413
复制
发表时间：
2013-04-01
期刊：
影响因子：
4.5
通讯作者：
Samson, Leona D.
中科院分区：
文献类型：
--
作者：
Calvo, Jennifer A.;Moroski-Erkul, Catherine A.;Samson, Leona D.
烷化剂包括主要类别的一线癌症化学治疗化合物，并且虽然这些药剂有效地杀死肿瘤细胞，但它们也损害健康组织。虽然碱基切除修复（BER）在修复DNA烷基化损伤中是必不可少的，但在某些条件下，BER的启动可能是有害的。在这里，我们说明，烷基腺嘌呤DNA糖基化酶（AAG）介导的烷基化诱导的组织损伤和整个动物的致死性暴露于烷化剂。在野生型小鼠中检测到Aag依赖性组织损伤，如在小脑颗粒细胞、脾细胞、胸腺细胞、骨髓细胞、胰腺β细胞和视网膜感光细胞中观察到的，在Aag转基因小鼠中加重，在Aag（-/-）小鼠中完全抑制。另外的遗传实验剖析了调节BER和Parp 1对小鼠烷基化敏感性的影响，并确定了Aag在烷基化诱导的组织损伤中作用于Parp 1的上游;事实上，在不存在Parp 1的情况下，WT和Aag转基因小鼠的细胞毒性被废除。这些结果提供了体内证据，表明Aag引发的BER可能在确定烷化剂化疗的副作用中起关键作用，并且Parp 1在Aag介导的组织损伤中起关键作用。
Alkylating agents comprise a major class of front-line cancer chemotherapeutic compounds, and while these agents effectively kill tumor cells, they also damage healthy tissues. Although base excision repair (BER) is essential in repairing DNA alkylation damage, under certain conditions, initiation of BER can be detrimental. Here we illustrate that the alkyladenine DNA glycosylase (AAG) mediates alkylation-induced tissue damage and whole-animal lethality following exposure to alkylating agents. Aag-dependent tissue damage, as observed in cerebellar granule cells, splenocytes, thymocytes, bone marrow cells, pancreatic beta-cells, and retinal photoreceptor cells, was detected in wild-type mice, exacerbated in Aag transgenic mice, and completely suppressed in Aag(-/-) mice. Additional genetic experiments dissected the effects of modulating both BER and Parp1 on alkylation sensitivity in mice and determined that Aag acts upstream of Parp1 in alkylation-induced tissue damage; in fact, cytotoxicity in WT and Aag transgenic mice was abrogated in the absence of Parp1. These results provide in vivo evidence that Aag-initiated BER may play a critical role in determining the side-effects of alkylating agent chemotherapies and that Parp1 plays a crucial role in Aag-mediated tissue damage.