BLM protein mitigates formaldehyde-induced genomic instability.
BLM protein mitigates formaldehyde-induced genomic instability.
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DOI：
10.1016/j.dnarep.2015.02.010
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发表时间：
2015-04
期刊：
影响因子：
3.8
通讯作者：
McCullough, Amanda K.
中科院分区：
文献类型：
--
作者：
Kumari, Anuradha;Owen, Nichole;Juarez, Eleonora;McCullough, Amanda K.
甲醛是一种活性醛，已被国际癌症研究机构列为I类人类致癌物。人们越来越关注与职业和环境人类暴露于甲醛有关的可能的不良健康影响。虽然甲醛诱导的DNA和蛋白质加合物已被确定，基因组不稳定性机制和与甲醛暴露相关的细胞耐受性途径尚未完全表征。本研究专门研究了基因组稳定性蛋白Bloom（BLM）在限制甲醛诱导的细胞和遗传异常中的作用。在这里，我们表明，在BLM蛋白的情况下，甲醛处理的细胞表现出增加的细胞敏感性，立即细胞周期停滞，和染色体放射状结构的积累。此外，活细胞成像实验表明，甲醛处理的细胞依赖于BLM及时分离的子细胞。野生型和BLM缺陷型福尔马林处理的细胞均显示53BP1和γ H2AX聚集灶，表明DNA双链断裂（DSB）;然而，相对于野生型细胞，BLM缺陷型细胞表现出延迟修复。在甲醛暴露的反应中，我们观察到53BP1和BLM病灶在DSB修复位点的共定位，其中在53BP1募集后发生了ATM依赖性的甲醛诱导的BLM病灶的积累。总之，这些发现突出了ATM，53BP1和BLM蛋白之间的功能相互作用的重要性，这些蛋白作为与甲醛诱导的修复和耐受机制相关的应答者。
Formaldehyde is a reactive aldehyde that has been classified as a class I human carcinogen by the International Agency for Cancer Research. There are growing concerns over the possible adverse health effects related to the occupational and environmental human exposures to formaldehyde. Although formaldehyde-induced DNA and protein adducts have been identified, the genomic instability mechanisms and the cellular tolerance pathways associated with formaldehyde exposure are not fully characterized. This study specifically examines the role of a genome stability protein, Bloom (BLM) in limiting formaldehyde-induced cellular and genetic abnormalities. Here, we show that in the absence of BLM protein, formaldehyde-treated cells exhibited increased cellular sensitivity, an immediate cell cycle arrest, and an accumulation of chromosome radial structures. In addition, live-cell imaging experiments demonstrated that formaldehyde-treated cells are dependent on BLM for timely segregation of daughter cells. Both wild-type and BLM-deficient formaldehyde-treated cells showed an accumulation of 53BP1 and γH2AX foci indicative of DNA double-strand breaks (DSBs); however, relative to wild-type cells, the BLM-deficient cells exhibited delayed repair. In response to formaldehyde exposure, we observed co-localization of 53BP1 and BLM foci at the DSB repair site, where ATM-dependent accumulation of formaldehyde-induced BLM foci occurred after the recruitment of 53BP1. Together, these findings highlight the significance of functional interactions among ATM, 53BP1, and BLM proteins as responders associated with the repair and tolerance mechanisms induced by formaldehyde.
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影响因子：
5.6
作者：
Mccabe, Kevin M.;Olson, Susan B.;Moses, Robb E.
通讯作者：
Moses, Robb E.
DOI：
10.1006/faat.1994.1137
发表时间：
1994-11-01
期刊：
FUNDAMENTAL AND APPLIED TOXICOLOGY
影响因子：
--
作者：
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通讯作者：
HECK, HD
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作者：
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通讯作者：
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影响因子：
21.3
作者：
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通讯作者：
Hickson, Ian D.
影响因子：
5
作者：
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通讯作者：
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