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Review
. 2020 Aug;61(7):730-735.
doi: 10.1002/em.22397. Epub 2020 Jul 22.

Roles of Chk2/CHEK2 in guarding against environmentally induced DNA damage and replication-stress

Md Kawsar Mustofa  1 , Yuki Tanoue  1 , Chie Tateishi  1 , Cyrus Vaziri  2 , Satoshi Tateishi  1
Affiliations
Review

Roles of Chk2/CHEK2 in guarding against environmentally induced DNA damage and replication-stress

Md Kawsar Mustofa et al. Environ Mol Mutagen. 2020 Aug.

Abstract

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.

Keywords: CHEK2; Chk2; RAD18; replication-associated DNA genotoxicity; translesion synthesis.

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