CHEK2

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Checkpoint kinase 2
Protein CHEK2 PDB 1gxc.png
PDB rendering based on 1gxc[1].
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CHEK2 ; CDS1; CHK2; HuCds1; LFS2; PP1425; RAD53; hCds1
External IDs OMIM604373 MGI1355321 HomoloGene38289 IUPHAR: 1988 ChEMBL: 2527 GeneCards: CHEK2 Gene
EC number 2.7.11.1
RNA expression pattern
PBB GE CHEK2 210416 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 11200 50883
Ensembl ENSG00000183765 ENSMUSG00000029521
UniProt O96017 Q9Z265
RefSeq (mRNA) NM_001005735 NM_016681
RefSeq (protein) NP_001005735 NP_057890
Location (UCSC) Chr 22:
29.08 – 29.14 Mb
Chr 5:
110.84 – 110.87 Mb
PubMed search [1] [2]

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

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.[2]

Gene location[edit]

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 base pair 28,687,742 to base pair 28,741,904.[2]

Protein structure[edit]

The CHK2 protein encoded by the CHEK2 gene is a serine threonine kinase. The protein consists of 543 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 phosphorylation in response to DNA damage. The most notable and frequently phosphorylated site being Thr68.[3]

CHK2 appears as a monomer in its inactive state. However, in the event of DNA damage SCD 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.[3]

Function and mechanism[edit]

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

When DNA undergoes a double-stand break or a related lesion due to either a natural occurrence or exposure to a toxic chemical, 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.[3] Once activated CHK2 phosphorylates downstream targets including CDC25 phosphatases, responsible for dephosphorylating and activating the cyclin-dependent kinases (CDKs). Thus, CHK2’s inhibition of the CDC25 phosphatases prevents entry of the cell into 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 E2F1 and the promyelocytic leukemia protein (PML) involved in apoptosis (programmed cell death).[3]

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 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.[2]

Discovery of association with cancer[edit]

In 1999 genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility.[4]

Bell et al. (1999) discovered three CHEK2 germline mutations among four Li-Fraumeni syndrome (LFS) and 18 Li-Fraumeni-like (LFL) families. This discovery indicated that mutations to the CHEK2 gene could predispose patients to Li-Fraumeni syndrome. Since the time of this discovery two of the three variants (a deletion in the kinase domain in exon 10 and a missense mutation in the FHA domain in exon 3) have been linked to inherited susceptibility to breast as well as other cancers.[5]

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 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.[5]

Mutations and cancer risk[edit]

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.

CHEK2 and breast cancer[edit]

Inherited mutations in the CHEK2 gene have been linked to certain cases of breast cancer. Most notably, the deletion of a single DNA 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.[2] 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.[6] 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.[7]

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.[5]

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.[6]

CHEK2 and other cancers[edit]

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 osteosarcoma.[2]

Unlike BRCA1 and BRCA2 mutations, CHEK2 mutations do not appear to cause an elevated risk for ovarian cancer.[7]

Meiosis[edit]

CHEK2 regulates cell cycle progression and spindle assembly during mouse oocyte maturation and early embryo development.[8] 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 meiosis. The response of oocytes to DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activates p53 and p63 proteins.[9]

In the fruitfly Drosophila, irradiation of germ line cells generates double-strand breaks that result in cell cycle arrest and apoptosis. The Drosophila CHEK2 ortholog mnk and the p53 ortholog dp53 are required for much of the cell death observed in early oogenesis when oocyte selection and meiotic recombination occur.[10]

Interactions[edit]

CHEK2 has been shown to interact with PLK1,[11] MDC1,[12] MSH2,[13][14] GINS2,[15] PLK3,[16] MUS81[17] and BRCA1.[18][19]

References[edit]

  1. ^ Li, J.; Williams, B. L.; Haire, L. F.; Goldberg, M.; Wilker, E.; Durocher, D.; Yaffe, M. B.; Jackson, S. P.; Smerdon, S. J. (2002). "Structural and functional versatility of the FHA domain in DNA-damage signaling by the tumor suppressor kinase Chk2". Molecular cell 9 (5): 1045–1054. doi:10.1016/S1097-2765(02)00527-0. PMID 12049740.  edit
  2. ^ a b c d e f g "CHEK2". Genetics Home Reference. August 2007. 
  3. ^ a b c d Cai Z, Chehab NH, Pavletich NP (September 2009). "Structure and Activation Mechanism of the CHK2 DNA Damage Checkpoint Kinase". Molecular Cell 35 (6): 818–829. doi:10.1016/j.molcel.2009.09.007. 
  4. ^ Bell DW et al. (December 1999). "Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome". Science 286 (5449): 2528–2531. doi:10.1126/science.286.5449.2528. PMID 10617473. 
  5. ^ a b c Nevanlinna H, Bartek J (2006). "The CHEK2 gene and inherited breast cancer susceptibility". Oncogene 25: 5912–5919. doi:10.1038/sj.onc.1209877. 
  6. ^ a b Offit K, Garber JE (February 2008). "Time to Check CHEK2 in Families With Breast Cancer?". Journal of Clinical Oncology 26 (4): 519–520. doi:10.1200/JCO.2007.13.8503. 
  7. ^ a b Meijers-Heijboer H et al. (2002). "Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations". Nature Genetics 31: 55–59. doi:10.1038/ng879. PMID 11967536. 
  8. ^ Dai XX, Duan X, Liu HL, Cui XS, Kim NH, Sun SC (2014). "Chk2 regulates cell cycle progression during mouse oocyte maturation and early embryo development". Mol. Cells 37 (2): 126–32. doi:10.14348/molcells.2014.2259. PMC 3935625. PMID 24598997. 
  9. ^ Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC (2014). "Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway". Science 343 (6170): 533–6. doi:10.1126/science.1247671. PMC 4048839. PMID 24482479. 
  10. ^ Shim HJ, Lee EM, Nguyen LD, Shim J, Song YH (2014). "High-dose irradiation induces cell cycle arrest, apoptosis, and developmental defects during Drosophila oogenesis". PLoS ONE 9 (2): e89009. doi:10.1371/journal.pone.0089009. PMC 3923870. PMID 24551207. 
  11. ^ Tsvetkov, Lyuben; Xu Xingzhi; Li Jia; Stern David F (March 2003). "Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody". J. Biol. Chem. (United States) 278 (10): 8468–75. doi:10.1074/jbc.M211202200. ISSN 0021-9258. PMID 12493754. 
  12. ^ Lou, Zhenkun; Minter-Dykhouse Katherine, Wu Xianglin, Chen Junjie (February 2003). "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways". Nature (England) 421 (6926): 957–61. doi:10.1038/nature01447. ISSN 0028-0836. PMID 12607004. 
  13. ^ Adamson, Aaron W; Beardsley Dillon I; Kim Wan-Ju; Gao Yajuan; Baskaran R; Brown Kevin D (March 2005). "Methylator-induced, Mismatch Repair-dependent G2 Arrest Is Activated through Chk1 and Chk2". Mol. Biol. Cell (United States) 16 (3): 1513–26. doi:10.1091/mbc.E04-02-0089. ISSN 1059-1524. PMC 551512. PMID 15647386. 
  14. ^ Brown, Kevin D; Rathi Abhilasha; Kamath Ravindra; Beardsley Dillon I; Zhan Qimin; Mannino Jennifer L; Baskaran R (January 2003). "The mismatch repair system is required for S-phase checkpoint activation". Nat. Genet. (United States) 33 (1): 80–4. doi:10.1038/ng1052. ISSN 1061-4036. PMID 12447371. 
  15. ^ Matsuoka, Shuhei; Ballif Bryan A, Smogorzewska Agata, McDonald E Robert, Hurov Kristen E, Luo Ji, Bakalarski Corey E, Zhao Zhenming, Solimini Nicole, Lerenthal Yaniv, Shiloh Yosef, Gygi Steven P, Elledge Stephen J (May 2007). "ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage". Science (United States) 316 (5828): 1160–6. doi:10.1126/science.1140321. PMID 17525332. 
  16. ^ Bahassi, El Mustapha; Conn Christopher W; Myer David L; Hennigan Robert F; McGowan Clare H; Sanchez Yolanda; Stambrook Peter J (September 2002). "Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways". Oncogene (England) 21 (43): 6633–40. doi:10.1038/sj.onc.1205850. ISSN 0950-9232. PMID 12242661. 
  17. ^ Chen, X B; Melchionna R; Denis C M; Gaillard P H; Blasina A; Van de Weyer I; Boddy M N; Russell P; Vialard J; McGowan C H (November 2001). "Human Mus81-associated endonuclease cleaves Holliday junctions in vitro". Mol. Cell (United States) 8 (5): 1117–27. doi:10.1016/S1097-2765(01)00375-6. ISSN 1097-2765. PMID 11741546. 
  18. ^ Lee, J S; Collins K M; Brown A L; Lee C H; Chung J H (March 2000). "hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response". Nature (ENGLAND) 404 (6774): 201–4. doi:10.1038/35004614. ISSN 0028-0836. PMID 10724175. 
  19. ^ Chabalier-Taste, Corinne; Racca Carine; Dozier Christine; Larminat Florence (December 2008). "BRCA1 is regulated by Chk2 in response to spindle damage". Biochim. Biophys. Acta (Netherlands) 1783 (12): 2223–33. doi:10.1016/j.bbamcr.2008.08.006. ISSN 0006-3002. PMID 18804494. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.