Checkpoint kinase 2 (human CHEK2; murine Chk2) is a critical mediator of the DNA damage response and has established roles in DNA double strand break (DSB)‐induced apoptosis and cell cycle arrest. DSBs may be invoked directly by ionizing radiation but may also arise indirectly from environmental exposures such as solar ultraviolet (UV) radiation. The primary forms of DNA damage induced by UV are DNA photolesions (such as cyclobutane pyrimidine dimers CPD and 6‐4 photoproducts) which interfere with DNA synthesis and lead to DNA replication fork stalling. Persistently stalled and unresolved DNA replication forks can “collapse” to generate DSBs that induce signaling via Chk2 and its upstream activator the ataxia telangiectasia‐mutated (ATM) protein kinase. This review focuses on recently defined roles of Chk2 in protecting against DNA replication‐associated genotoxicity. Several DNA damage response factors such as Rad18, Nbs1 and Chk1 suppress stalling and collapse of DNA replication forks. Defects in the primary responders to DNA replication fork stalling lead to generation of DSB and reveal “back‐up” roles for Chk2 in S‐phase progression and genomic stability. In humans, there are numerous variants of the CHEK2 gene, including CHEK2*1100delC. Individuals with the CHEK2*1100delC germline alteration have an increased risk of developing breast cancer and malignant melanoma. DNA replication fork‐stalling at estrogen‐DNA adducts and UV‐induced photolesions are implicated in the etiology of breast cancer and melanoma, respectively. It is likely therefore that the Chk2/CHEK2‐deficiency is associated with elevated risk for tumorigenesis caused by replication‐associated genotoxicities that are exacerbated by environmental genotoxins and intrinsic DNA‐damaging agents.

中文翻译：

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Chk2 / CHEK2在预防环境诱导的DNA损伤和复制压力中的作用。

Checkpoint激酶2（人类CHEK2;鼠Chk2）是DNA损伤反应的关键介体，并在DNA双链断裂（DSB）诱导的细胞凋亡和细胞周期停滞中发挥了重要作用。DSB可以通过电离辐射直接调用，但也可以间接源自环境暴露，例如太阳紫外线（UV）辐射。紫外线引起的DNA损伤的主要形式是DNA光损伤（例如环丁烷嘧啶二聚体CPD和6-4光产物），它们会干扰DNA合成并导致DNA复制叉停滞。持续停滞和未解决的DNA复制叉可能会“折叠”以生成DSB，从而通过Chk2及其上游激活剂诱导共济失调性毛细血管扩张突变（ATM）蛋白激酶。这篇综述着重介绍了Chk2在防止DNA复制相关的遗传毒性中的最新定义。Rad18，Nbs1和Chk1等几种DNA损伤反应因子可抑制DNA复制叉的停滞和塌陷。DNA复制叉停滞的主要应答者的缺陷导致DSB的产生，并揭示了Chk2在S期进程和基因组稳定性中的“备份”作用。在人类中，有许多CHEK2基因，包括CHEK2 * 1100delC。CHEK2 * 1100delC种系发生改变的个体患乳腺癌和恶性黑色素瘤的风险增加。乳腺癌和黑色素瘤的病因学分别涉及雌激素-DNA加合物的DNA复制和紫外线诱导的光损伤。因此，Chk2 / CHEK2缺乏可能与由复制相关的基因毒性引起的肿瘤发生风险升高有关，而环境遗传毒素和内在的DNA破坏剂加剧了这种毒性。