DNA damage response and tumorigenesis in Mcm2-deficient mice.
DNA damage response and tumorigenesis in Mcm2-deficient mice.
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DOI：
10.1038/onc.2010.125
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发表时间：
2010-06-24
期刊：
影响因子：
8
通讯作者：
Pruitt SC
中科院分区：
文献类型：
--
作者：
Kunnev D;Rusiniak ME;Kudla A;Freeland A;Cady GK;Pruitt SC
微型染色体维持蛋白（Mcm's）是DNA复制许可复合物的组成部分。在体内，Mcm蛋白的表达或活性降低已被证明会导致高度渗透性的早发性癌症（和干细胞缺陷）。在这里，我们使用来自Mcm 2缺陷型小鼠品系的MEFs，通过DNA纤维分析显示，在HU介导的复制应激条件下，Mcm 2缺陷型细胞中的起点使用减少。还检查了由HU和其他复制依赖性和非复制性遗传毒性剂引起的DNA损伤反应（DDR），并显示其在野生型水平下发挥作用。此外，DNA损伤反应的许多组分的基础水平以野生型水平表达，表明在正常生长条件下不存在急性复制应激。仅发现γ-H2 AX、p21 cip 1和53 bp灶的基础水平非常适度地增加1.5-2倍，这与DDR途径的轻微慢性升高一致。一个条件，其中wt和Mcm 2缺陷细胞之间的差异较大，发现发生在紫外线照射后，可能反映了Chk 1介导的抑制休眠起源的作用。在体内，废除Mcm 2缺陷小鼠中的p53介导的DDR导致存活小鼠中胚胎致死率增加和癌症形成加速。此外，p53突变挽救了Mcm 2缺陷对体外神经干细胞存活的负面影响;然而，相对于携带p53突变的Mcm 2 wt细胞，增强的存活与增加的遗传损伤相关。总之，这些结果表明，即使是相对较小的干扰初级或休眠复制起点的使用有助于加速体内遗传损伤。此外，这些研究表明，由Mcm 2缺陷引起的肿瘤类型受到遗传背景和p53相互作用的强烈影响。
Mini-chromosome maintenance proteins (Mcm’s) are components of the DNA replication licensing complex. In vivo, reduced expression or activity of Mcm proteins has been shown to result in highly penetrant early onset cancers ( and stem cell deficiencies. Here we use MEFs from an Mcm2 deficient strain of mice to show by DNA fiber analysis that origin usage is decreased in Mcm2 deficient cells under conditions of HU mediated replication stress. DNA damage responses (DDR) resulting from HU and additional replication dependent and independent genotoxic agents were also examined and shown to function at wild type levels. Further, basal levels of many components of the DNA damage response were expressed at wild type levels demonstrating that there is no acute replicative stress under normal growth conditions. Only very modest, 1.5–2 fold increases in the basal levels of γ-H2AX, p21cip1 and 53bp foci were found, consistent with a slight chronic elevation in DDR pathways. The one condition in which a larger difference between wt and Mcm2 deficient cells was found occurred following UV irradiation and may reflect the role of Chk1 mediated suppression of dormant origins. In vivo, abrogating p53 mediated DDR in Mcm2 deficient mice results in increased embryonic lethality and accelerated cancer formation in surviving mice. Further, p53 mutation rescues the negative effect of Mcm2 deficiency on the survival of neural stem cells in vitro; however, the enhanced survival correlates with increased genetic damage relative to Mcm2 wt cells carrying the p53 mutation. Together these results demonstrate that even relatively minor perturbations to primary or dormant replication origin usage contribute to accelerated genetic damage in vivo. Additionally, these studies demonstrate that tumor types resulting from Mcm2 deficiency are strongly affected by interaction with both genetic background and p53.
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影响因子：
7.8
作者：
Bailey, KJ;Maslov, AY;Pruitt, SC
通讯作者：
Pruitt, SC
影响因子：
5.3
作者：
Maslov, AY;Barone, TA;Pruitt, SC
通讯作者：
Pruitt, SC
DOI：
10.4161/cc.8.1.7528
发表时间：
2009-01-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Liu P;Slater DM;Lenburg M;Nevis K;Cook JG;Vaziri C
通讯作者：
Vaziri C
影响因子：
10.5
作者：
Ge, Xin Quan;Jackson, Dean A;Blow, J Julian
通讯作者：
Blow, J Julian
DOI：
10.1038/nrm1663
发表时间：
2005-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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