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CHK2

Official Full Name
checkpoint kinase 2
Organism
Homo sapiens
GeneID
11200
Background
In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Synonyms
CDS1; CHK2; LFS2; RAD53; TPDS4; hCds1; HuCds1; PP1425;
Bio Chemical Class
Kinase
Protein Sequence
MSRESDVEAQQSHGSSACSQPHGSVTQSQGSSSQSQGISSSSTSTMPNSSQSSHSSSGTLSSLETVSTQELYSIPEDQEPEDQEPEEPTPAPWARLWALQDGFANLECVNDNYWFGRDKSCEYCFDEPLLKRTDKYRTYSKKHFRIFREVGPKNSYIAYIEDHSGNGTFVNTELVGKGKRRPLNNNSEIALSLSRNKVFVFFDLTVDDQSVYPKALRDEYIMSKTLGSGACGEVKLAFERKTCKKVAIKIISKRKFAIGSAREADPALNVETEIEILKKLNHPCIIKIKNFFDAEDYYIVLELMEGGELFDKVVGNKRLKEATCKLYFYQMLLAVQYLHENGIIHRDLKPENVLLSSQEEDCLIKITDFGHSKILGETSLMRTLCGTPTYLAPEVLVSVGTAGYNRAVDCWSLGVILFICLSGYPPFSEHRTQVSLKDQITSGKYNFIPEVWAEVSEKALDLVKKLLVVDPKARFTTEEALRHPWLQDEDMKRKFQDLLSEENESTALPQVLAQPSTSRKRPREGEAEGAETTKRPAVCAAVL
Open
Disease
Solid tumour/cancer
Approved Drug
0
Clinical Trial Drug
1 +
Discontinued Drug
1 +

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Detailed Information

During the cell lifecycle, DNA damage and replication obstacles often lead to disruptions in the cell cycle process. To counter these threats, cells employ a series of essential cell cycle regulators to halt cell division, ensuring damaged cells are repaired or eliminated. Among these regulators, the protein encoded by the CHEK2 gene plays a crucial role in responding to DNA damage and replication issues and is considered a cell cycle checkpoint regulator and potential tumor suppressor. This article provides a detailed overview of the function of the CHEK2 gene, its relationship with cancer, and current research progress.

Figure 1 illustrates how CHK2 kinase, activated by ATM phosphorylation in response to DNA damage, regulates cell-cycle checkpoints, apoptosis, and DNA repair through phosphorylation of substrates like p53 and BRCA1.Figure 1. Regulation and function of CHK2 Kinase in DNA damage response.

CHEK2 Gene and Protein Function

Acting via phosphorylation of a sequence of downstream targets, this protein is quickly triggered in response to DNA damage or replication restrictions. When a cell experiences DNA double-stranded breaks, CHEK2 is triggered by the upstream ATM kinase and subsequently phosphorylates important proteins like the cell division cycle protein CDC25C and BRCA1, therefore stopping cell cycle progression and bringing cells to arrest in the G1 phase. Through phosphorylation, CHEK2 may also stabilize tumor suppressors such p53, therefore starting cell cycle arrest or guiding cells toward programmed cell death. By means of these control systems, CHEK2 is essential in avoiding genomic instability and cancer formation.

Apart from DNA repair and cell cycle regulation, the CHEK2 protein serves autophagy in response to environmental stressors like oxidative stress. By phosphorylating the E3 ubiquitin ligase TRIM32, CHEK2 may induce the ubiquitination of ATG7, therefore controlling autophagosome generation—a process with great consequences for cancer cell development and survival.

Relationship between CHEK2 and Cancer

Widely accepted as a tumor suppressor gene, CHEK2 has mutations closely linked to many cancer types. People with CHEK2 mutations generally show higher cancer susceptibility, most especially higher risks for thyroid, kidney, and breast cancers.

Research has shown a clear correlation between CHEK2 gene alterations and the incidence of breast cancer. Compared to the general population, female CHEK2 gene carriers had more than double the chance of acquiring breast cancer. Studies conducted by the National Institutes of Health (NIH) indicate that women with CHEK2 mutations—especially those with "truncating" types—have notably higher breast cancer risks. Particularly specific CHEK2 mutations like c.1100del have been linked to breast cancer sensitivity.

Apart from breast cancer, CHEK2 mutations have also been associated with tumors including kidney cancer, thyroid cancer, and osteosarcoma. Moreover, certain brain cancers and soft tissue sarcomas might be very linked with CHEK2 malfunction. Though the relationship between CHEK2 mutations and colorectal or prostate cancer is yet unknown, those who have these genes generally need more regular tests to spot any cancer that develops early on.

Genetic Susceptibility and Cancer Risk

Those with CHEK2 mutations usually have a 50% likelihood of transmitting these mutations on to the next generation. This emphasizes the need of knowing family histories of CHEK2 gene mutations in order to help high-risk people in early screening and risk assessment to implement suitable preventive actions.

Clinically significant CHEK2 gene mutations: Growing knowledge of CHEK2 mutations has come from advancing genomic studies. Especially in the categorization of genomic changes, scientists are creating a set of functional tests to evaluate how these mutations influence CHEK2 protein activity.

Clinical Assessment of Missense Mutations: Missense mutations involve changes in the gene sequence leading to amino acid changes, often affecting protein function. Some missense mutations lead to decreased stability or weakened kinase activity of the CHEK2 protein, impacting its role in DNA repair and cell cycle control. Recent research through various functional assays has found strong relationships between these missense mutations and the risk of diseases like breast cancer.

Functional Assays and Cancer Risk Assessment: For CHEK2 missense mutations, functional assays can help clinicians more accurately assess their clinical significance. Using multiple experimental systems, such as yeast and mammalian cell lines, researchers can functionally validate different CHEK2 variants, determining which mutations lead to functional loss in proteins thus increasing cancer risk. These findings aid in providing individuals with these mutations more precise risk assessments and management plans.

Future Prospects and Research Directions

With the continuous advancement of gene testing technologies, clinical detection of CHEK2 gene mutations and cancer risk prediction will become more precise. Future research will focus more on revealing additional CHEK2 mutation types associated with cancer development through large-scale functional genomic analyses. Additionally, CRISPR/Cas9-based genetic editing tools offer powerful means to explore how these mutations impact cell growth and division at the genomic level.

Precise Assessment of Functional Mutations: While we have some understanding of CHEK2 mutation types, their specific functional impacts require further validation. As new experimental technologies and data analysis methods develop, we can more precisely predict the effects of different mutations on protein function, consequently enhancing the sensitivity of clinical screening.

Personalized Treatment and Prevention Strategies: For high-risk populations carrying CHEK2 mutations, future personalized medicine will offer more prevention and treatment options. By combining genetic testing with individual clinical backgrounds, doctors can develop more suitable screening plans and personalized cancer prevention or treatment strategies for patients.

References:

  1. Boonen RACM, Vreeswijk MPG, et al. CHEK2 variants: linking functional impact to cancer risk. Trends Cancer. 2022 Sep;8(9):759-770.
  2. Stolarova L, Kleiblova P, et al., CHEK2 Germline Variants in Cancer Predisposition: Stalemate Rather than Checkmate. Cells. 2020 Dec 12;9(12):2675.
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