CHEK2

CHEK2 is the official symbol for the human is_associated_with::gene Checkpoint kinase 2. CHEK2 is located on the long (q) arm of chromosome 22. CHEK2 is is_associated_with::tumor suppressor gene that encodes the is_associated_with::protein CHK2, a serine threonine kinase. CHK2 operates in an intricate network of proteins to elicit is_associated_with::DNA repair, cell cycle arrest or is_associated_with::apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of is_associated_with::cancers including is_associated_with::breast cancer.

Other names for CHK2 include CDS1, Cds1 kinase, checkpoint-like protein CHK2, CHK2, CHK2 checkpoint homolog, CHK2_HUMAN, Chk2 protein kinase, hCds1 protein, hCHK2, HuCds1, RAD53, serine/threonine-protein kinase CHK2.

Gene location
The CHEK2 gene is located on the long (q) arm of chromosome 22 at position 12.1. In other words, its location of chromosome 22 stretches from is_associated_with::base pair 28,687,742 to base pair 28,741,904.

Protein structure
The CHK2 protein encoded by the CHEK2 gene is a serine threonine kinase. The protein consists of 543 is_associated_with::amino acids and the following domains:
 * N-terminal SQ/TQ cluster doman (SCD)
 * Central forkhead-associated (FHA) domain
 * C-terminal serine/threonine kinase domain (KD)

The SCD domain contains multiple SQ/TQ motifs that serve as sites for is_associated_with::phosphorylation in response to is_associated_with::DNA damage. The most notable and frequently phosphorylated site being Thr68.

CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCD is_associated_with::phosphorylation causes CHK2 dimerization. The phosphorylated Thr68 (located on the SCD) interacts with the FHA domain to form the dimer. After the protein dimerizes the KD is activated via autophosphorylation. Once the KD is activated the CHK2 dimer dissociates.

Function and mechanism
The CHEK2 gene provides instructions for making checkpoint kinase 2 (CHK2), a protein that acts a tumor suppressor. CHK2 regulates is_associated_with::cell division. More specifically CHK2 has the ability to prevent cells from dividing too rapidly or in an uncontrolled manner.

When DNA undergoes a double-stand break or a related lesion due to either a natural occurrence or exposure to a toxic chemical, is_associated_with::radiation or UV rays the CHK2 protein is activated. Specifically, DNA damage-activated phosphatidylinositol kinase family protein (PIKK) ATM phosphorylates site Thr68 and activates CHK2. Once activated CHK2 phosphorylates downstream targets including is_associated_with::CDC25 phosphatases, responsible for dephosphorylating and activating the is_associated_with::cyclin-dependent kinases (CDKs). Thus, CHK2’s inhibition of the CDC25 phosphatases prevents entry of the cell into is_associated_with::mitosis. Furthermore, the CHK2 protein interacts with several other proteins including p53 (p53). Stabilization of p53 by CHK2 leads to cell cycle arrest in phase G1. Furthermore, CHK2 is known to phosphorylate the cell-cycle transcription factor is_associated_with::E2F1 and the is_associated_with::promyelocytic leukemia protein (PML) involved in is_associated_with::apoptosis (programmed cell death).

CHK2, p53 and a combination of other tumor suppressor proteins freeze the cell division process and decide whether the damage will be repaired or if the cell will undergo apoptosis. If the damage is to be repaired, CHK2 interacts with and phosphorylates is_associated_with::BRCA1, a protein responsible for repairing damaged DNA. By preventing mutated or damaged DNA from being passed onto daughter cells, CHK2 helps stop tumors from developing.

Association with cancer
In 1999 genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility.

Bell et al. (1999) discovered three CHEK2 germline mutations among four is_associated_with::Li-Fraumeni syndrome (LFS) and 18 Li-Fraumeni-like (LFL) families. This discovery indicated that mutations to the CHEK2 gene could predispose patients to is_associated_with::Li-Fraumeni syndrome. Since the time of this discovery two of the three variants (a deletion in the kinase domain in is_associated_with::exon 10 and a is_associated_with::missense mutation in the FHA domain in is_associated_with::exon 3) have been linked to inherited susceptibility to breast as well as other cancers.

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 on is_associated_with::exon 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.

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.

Breast cancer
Inherited mutations in the CHEK2 gene have been linked to certain cases of is_associated_with::breast cancer. Most notably, the deletion of a single DNA is_associated_with::nucleotide 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. 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 virtually absent in Spain and India. 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.

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.

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 the Ashkenazi Jewish population.

Other cancers
Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer. A full range of cancers has not been determined but studies link the mutation to cases of prostate, lung, colon, kidney, and thyroid cancers. Links have also been drawn to certain brain tumors and is_associated_with::osteosarcoma.

Unlike is_associated_with::BRCA1 and is_associated_with::BRCA2 mutations, CHEK2 mutations do not appear to cause an elevated risk for is_associated_with::ovarian cancer.

Meiosis
CHEK2 regulates is_associated_with::cell cycle progression and spindle assembly during mouse is_associated_with::oocyte maturation and early is_associated_with::embryo development. Although CHEK2 is a down stream effector of the ATM kinase that responds primarily to double-strand breaks it can also be activated by ATR (ataxia-telangiectasia and Rad3 related) kinase that responds primarily to single-strand breaks. In mouse, CHEK2 is essential for DNA damage surveillance in female is_associated_with::meiosis. The response of is_associated_with::oocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activates is_associated_with::p53 and p63 proteins.

In the fruitfly Drosophila, irradiation of germ line cells generates double-strand breaks that result in cell cycle arrest and is_associated_with::apoptosis. The Drosophila CHEK2 ortholog mnk and the is_associated_with::p53 ortholog dp53 are required for much of the cell death observed in early is_associated_with::oogenesis when oocyte selection and meiotic recombination occur.

Interactions
CHEK2 has been shown to interact with:


 * is_associated_with::BRCA1,
 * is_associated_with::GINS2,
 * is_associated_with::MDC1,
 * is_associated_with::MSH2,
 * is_associated_with::MUS81
 * is_associated_with::PLK1, and
 * is_associated_with::PLK3.