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DNA damage signaling in the cellular responses to mustard vesicants
Toxicology Letters ( IF 3.5 ) Pub Date : 2020-06-01 , DOI: 10.1016/j.toxlet.2020.03.008
Yi-Hua Jan 1 , Diane E Heck 2 , Debra L Laskin 3 , Jeffrey D Laskin 1
Affiliation  

Mustard vesicants, including sulfur mustard (2,2'-dichlorodiethyl sulfide, SM) and nitrogen mustard (bis(2-chloroethyl)methylamine, HN2) are cytotoxic blistering agents synthesized for chemical warfare. Because they contain highly reactive electrophilic chloroethyl side chains, they readily react with cellular macromolecules like DNA forming monofunctional and bifunctional adducts. By targeting DNA, mustards can compromise genomic integrity, disrupt the cell cycle, and cause mutations and cytotoxicity. To protect against genotoxicity following exposure to mustards, cells initiate a DNA damage response (DDR). This involves activation of signaling cascades including ATM (ataxia telangiectasia mutated), ATR (ataxia telangiectasia and Rad3-related) and DNA-PKcs (DNA-dependent protein kinase, catalytic unit). Signaling induced by the DDR leads to the recruitment and activation of repair related proteins such as H2AX and p53 to sites of DNA lesions. Excessive DNA modifications by mustards can overwhelm DNA repair leading to single and double strand DNA breaks, cytotoxicity and tissue damage, sometimes leading to cancer. Herein we summarize DDR signaling pathways induced by SM, HN2 and the half mustard, 2-chloroethyl ethyl sulfide (CEES). At the present time, little is known about how mustard-induced DNA damage leads to the activation of DDR signaling. A better understanding of mechanisms by which mustard vesicants induce the DDR may lead to the development of countermeasures effective in mitigating tissue injury.

中文翻译:

DNA 损伤信号在细胞对芥末起泡剂的反应中

芥末起泡剂,包括硫芥(2,2'-二氯二乙基硫醚,SM)和氮芥(双(2-氯乙基)甲胺,HN2)是为化学战合成的细胞毒性起泡剂。因为它们含有高反应性的亲电子氯乙基侧链,它们很容易与细胞大分子(如 DNA)反应,形成单功能和双功能加合物。通过靶向 DNA,芥末会损害基因组完整性、破坏细胞周期并导致突变和细胞毒性。为了防止暴露于芥末后的基因毒性,细胞会启动 DNA 损伤反应 (DDR)。这涉及信号级联的激活,包括 ATM(共济失调毛细血管扩张突变)、ATR(共济失调毛细血管扩张和 Rad3 相关)和 DNA-PKcs(DNA 依赖性蛋白激酶,催化单元)。DDR 诱导的信号传导导致修复相关蛋白(如 H2AX 和 p53)募集和激活到 DNA 损伤位点。芥末过多的 DNA 修饰会破坏 DNA 修复,导致单链和双链 DNA 断裂、细胞毒性和组织损伤,有时会导致癌症。在此,我们总结了由 SM、HN2 和半芥子气、2-氯乙基乙基硫醚 (CEES) 诱导的 DDR 信号通路。目前,关于芥末诱导的 DNA 损伤如何导致 DDR 信号的激活知之甚少。更好地了解芥末起泡剂诱导 DDR 的机制可能会导致制定有效减轻组织损伤的对策。芥末过多的 DNA 修饰会破坏 DNA 修复,导致单链和双链 DNA 断裂、细胞毒性和组织损伤,有时会导致癌症。在此,我们总结了由 SM、HN2 和半芥子气、2-氯乙基乙基硫醚 (CEES) 诱导的 DDR 信号通路。目前,关于芥末诱导的 DNA 损伤如何导致 DDR 信号的激活知之甚少。更好地了解芥末起泡剂诱导 DDR 的机制可能会导致制定有效减轻组织损伤的对策。芥末过多的 DNA 修饰会破坏 DNA 修复,导致单链和双链 DNA 断裂、细胞毒性和组织损伤,有时会导致癌症。在此,我们总结了由 SM、HN2 和半芥子气、2-氯乙基乙基硫醚 (CEES) 诱导的 DDR 信号通路。目前,关于芥末诱导的 DNA 损伤如何导致 DDR 信号的激活知之甚少。更好地了解芥末起泡剂诱导 DDR 的机制可能会导致制定有效减轻组织损伤的对策。关于芥末诱导的 DNA 损伤如何导致 DDR 信号的激活知之甚少。更好地了解芥末起泡剂诱导 DDR 的机制可能会导致制定有效减轻组织损伤的对策。关于芥末诱导的 DNA 损伤如何导致 DDR 信号的激活知之甚少。更好地了解芥末起泡剂诱导 DDR 的机制可能会导致制定有效减轻组织损伤的对策。
更新日期:2020-06-01
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