The CHEK2 gene is located on the long (q) arm ofchromosome 22 at position 12.1. Its location on chromosome 22 stretches frombase pair 28,687,742 to base pair 28,741,904.[5]
The SCD domain contains multiple SQ/TQmotifs that serve as sites forphosphorylation in response toDNA damage. The most notable and frequently phosphorylated site being Thr68.[6]
CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCDphosphorylation causes CHK2dimerization. The phosphorylated Thr68 (located on the SCD) interacts with the FHA domain to form thedimer. After the protein dimerizes the KD is activated via autophosphorylation. Once the KD is activated the CHK2 dimer dissociates.[6]
The CHEK2 gene encodes for checkpoint kinase 2 (CHK2), a protein that acts as atumor suppressor. CHK2 regulatescell division, and has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.[5]
When DNA undergoes a double-strand break, CHK2 is activated. Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2.[6] Once activated, CHK2 phosphorylates downstream targets includingCDC25 phosphatases, responsible for dephosphorylating and activating thecyclin-dependent kinases (CDKs). Thus, CHK2's inhibition of the CDC25 phosphatases prevents entry of the cell intomitosis. Furthermore, the CHK2 protein interacts with several other proteins includingp53 (p53). Stabilization of p53 by CHK2 leads to cell cycle arrest inphase G1. Furthermore, CHK2 is known tophosphorylate the cell-cycle transcription factorE2F1 and thepromyelocytic leukemia protein (PML) involved inapoptosis (programmed cell death).[6]
The CHK2 protein plays a critical role in the DNA damage checkpoint. Thus, mutations to the CHEK2 gene have been labeled as causes to a wide range of cancers.
In 1999, genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility.[7]
Bell et al. (1999) discovered three CHEK2germline mutations among fourLi–Fraumeni syndrome (LFS) and 18 Li–Fraumeni-like (LFL) families. Since the time of this discovery, two of the three variants (a deletion in the kinase domain inexon 10 and amissense mutation in the FHA domain inexon 3) have been linked to inherited susceptibility to breast as well as other cancers.[8]
Beyond initial speculations, screening of LFS and LFL patients has revealed no or very rare individual missense variants in the CHEK2 gene. Additionally, the deletion in the kinase domain onexon 10 has been found rare among LFS/LFL patients. The evidence from these studies has suggests that CHEK2 is not a predisposition gene to Li–Fraumeni syndrome.[8]
Inherited mutations in the CHEK2 gene have been linked to certain cases ofbreast cancer. Most notably, the deletion of a single DNAnucleotide at position 1100 in exon 10 (1100delC) produces a nonfunctional version of the CHK2 protein, truncated at the kinase domain. The loss of normal CHK2 protein function leads to unregulated cell division, accumulated damage to DNA and in many cases,tumor development.[5] The CHEK2*1100del mutation is most commonly seen in individuals of Eastern and Northern European descent. Within these populations the CHEK2*1100delC mutation is seen in 1 out of 100 to 1 out of 200 individuals. However, in North America the frequency drops to 1 out of 333 to 1 out of 500. The mutation is almost absent in Spain and India.[9] Studies show that a CHEK2 1100delC corresponds to a two-fold increased risk of breast cancer and a 10-fold increased risk of breast cancer in males.[10]
A CHEK2 mutation known as the I157T variant to the FHA domain in exon 3 has also been linked to breast cancer but at a lower risk than the CHEK2*1100delC mutation. The estimated fraction of breast cancer attributed to this variant is reported to be around 1.2% in the US.[8]
Two more CHEK2 gene mutations, CHEK2*S428F, an amino-acid substitution to the kinase domain in exon 11 and CHEK2*P85L, an amino-acid substitution in the N-terminal region (exon 1) have been found in theAshkenazi Jewish population.[9] Suggestion of a Hispanic founder mutation has also been described.[11]
Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer. Studies link the mutation to cases ofprostate,lung,colon,kidney, andthyroid cancers. Links have also been drawn to certain brain tumors andosteosarcoma.[5]
UnlikeBRCA1 andBRCA2 mutations, CHEK2 mutations do not appear to cause an elevated risk forovarian cancer.[10] However, a large-effect genome-wide association forsquamous lung cancer has been described for a rare variant in CHEK2 (p.Ile157Thr, rs17879961, OR = 0.38).[12]
CHEK2 regulatescell cycle progression andspindle assembly during mouseoocyte maturation and earlyembryo development.[13][14] Although CHEK2 is a down stream effector of theATM kinase that responds primarily to double-strand breaks it can also be activated byATR (ataxia-telangiectasia and Rad3 related) kinase that responds primarily to single-strand breaks. In mice, CHEK2 is essential for DNA damage surveillance in femalemeiosis. The response ofoocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activatesp53 andp63 proteins.[15]
In the fruit flyDrosophila,irradiation ofgerm line cells generates double-strand breaks that result in cell cycle arrest andapoptosis. TheDrosophila CHEK2ortholog mnk and thep53ortholog dp53 are required for much of the cell death observed in earlyoogenesis when oocyte selection and meiotic recombination occur.[16]
^Ruth KS, Day FR, Hussain J, Martínez-Marchal A, Aiken CE, Azad A, et al. (August 2021). "Genetic insights into biological mechanisms governing human ovarian ageing". pp. 393–397.medRxiv10.1101/2021.01.11.20248322v1.
^Chabalier-Taste C, Racca C, Dozier C, Larminat F (December 2008). "BRCA1 is regulated by Chk2 in response to spindle damage".Biochimica et Biophysica Acta (BBA) - Molecular Cell Research.1783 (12):2223–33.doi:10.1016/j.bbamcr.2008.08.006.PMID18804494.
^Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R (January 2003). "The mismatch repair system is required for S-phase checkpoint activation".Nature Genetics.33 (1):80–4.doi:10.1038/ng1052.PMID12447371.S2CID20616220.
Peng CY, Graves PR, Thoma RS, Wu Z, Shaw AS, Piwnica-Worms H (September 1997). "Mitotic and G2 checkpoint control: regulation of 14-3-3 protein binding by phosphorylation of Cdc25C on serine-216".Science.277 (5331):1501–5.doi:10.1126/science.277.5331.1501.PMID9278512.
Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, et al. (December 1999). "Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome".Science.286 (5449):2528–31.doi:10.1126/science.286.5449.2528.PMID10617473.
