Wikipedia

CHEK2

CHEK2(Checkpoint kinase 2) is atumor suppressor genethat encodes theproteinCHK2,aserine-threonine kinase.CHK2 is involved inDNA repair,cell cycle arrest orapoptosisin response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range ofcancers.[5]

CHEK2
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesCHEK2,CDS1, CHK2, HuCds1, LFS2, PP1425, RAD53, hCds1, checkpoint kinase 2
External IDsOMIM:604373;MGI:1355321;HomoloGene:38289;GeneCards:CHEK2;OMA:CHEK2 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

11200

50883

Ensembl

ENSG00000183765

ENSMUSG00000029521

UniProt

O96017

Q9Z265

RefSeq (mRNA)

NM_001005735
NM_001257387
NM_007194
NM_145862
NM_001349956

NM_016681
NM_001363308

RefSeq (protein)

NP_001005735
NP_001244316
NP_009125
NP_665861
NP_001336885

NP_057890
NP_001350237

Location (UCSC)Chr 22: 28.69 – 28.74 MbChr 5: 110.99 – 111.02 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene location

edit

The CHEK2 gene is located on the long (q) arm ofchromosome 22at position 12.1. Its location on chromosome 22 stretches frombase pair28,687,742 to base pair 28,741,904.[5]

Protein structure

edit

The CHEK2 protein encoded by the CHEK2 gene is aserine threonine kinase.The protein consists of 543amino acidsand the followingdomains:

The SCD domain contains multiple SQ/TQmotifsthat serve as sites forphosphorylationin response toDNAdamage. 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 SCDphosphorylationcauses 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]

Function and mechanism

edit

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 includingCDC25phosphatases, 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 tophosphorylatethe cell-cycle transcription factorE2F1and thepromyelocytic leukemia protein(PML) involved inapoptosis(programmed cell death).[6]

Association with cancer

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.

In 1999, genetic variations of CHEK2 were found to correspond to inherited cancer susceptibility.[7]

Bell et al. (1999) discovered three CHEK2germline mutationsamong 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 inexon10 and amissense mutationin the FHA domain inexon3) 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 onexon10 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]

Breast cancer

edit

Inherited mutations in the CHEK2 gene have been linked to certain cases ofbreast cancer.Most notably, the deletion of a single DNAnucleotideat 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,tumordevelopment.[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 Jewishpopulation.[9]Suggestion of a Hispanic founder mutation has also been described.[11]

Other cancers

edit

Mutations to CHEK2 have been found in hereditary and nonhereditary cases of cancer. Studies link the mutation to cases ofprostate,lung,colon,kidney,andthyroidcancers. Links have also been drawn to certain brain tumors andosteosarcoma.[5]

UnlikeBRCA1andBRCA2mutations, CHEK2 mutations do not appear to cause an elevated risk forovarian cancer.[10]However, a large-effect genome-wide association forsquamous lung cancerhas been described for a rare variant in CHEK2 (p.Ile157Thr, rs17879961, OR = 0.38).[12]

Meiosis

edit

CHEK2 regulatescell cycleprogression andspindleassembly during mouseoocytematuration and earlyembryodevelopment.[13][14]Although CHEK2 is a down stream effector of theATMkinase 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 ofoocytesto DNA double-strand break damage involves a pathway hierarchy in which ATR kinase signals to CHEK2 which then activatesp53andp63proteins.[15]

In the fruit flyDrosophila,irradiationofgerm linecells generates double-strand breaks that result in cell cycle arrest andapoptosis.TheDrosophilaCHEK2orthologmnk and thep53orthologdp53 are required for much of the cell death observed in earlyoogenesiswhen oocyte selection and meiotic recombination occur.[16]

Interactions

edit

CHEK2 has been shown tointeractwith:

References

edit
  1. ^abcGRCh38: Ensembl release 89: ENSG00000183765–Ensembl,May 2017
  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000029521–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^abcde"CHEK2".Genetics Home Reference.August 2007.Archivedfrom the original on 2015-04-25.Retrieved2015-04-22.
  6. ^abcdCai Z, Chehab NH, Pavletich NP (September 2009)."Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase".Molecular Cell.35(6): 818–29.doi:10.1016/j.molcel.2009.09.007.PMID19782031.
  7. ^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.
  8. ^abcNevanlinna H, Bartek J (September 2006). "The CHEK2 gene and inherited breast cancer susceptibility".Oncogene.25(43): 5912–9.doi:10.1038/sj.onc.1209877.PMID16998506.S2CID7343321.
  9. ^abOffit K, Garber JE (February 2008)."Time to check CHEK2 in families with breast cancer?".Journal of Clinical Oncology.26(4): 519–20.doi:10.1200/JCO.2007.13.8503.PMID18172189.
  10. ^abMeijers-Heijboer H, van den Ouweland A, Klijn J, Wasielewski M, de Snoo A, Oldenburg R, et al. (May 2002)."Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations".Nature Genetics.31(1): 55–9.doi:10.1038/ng879.PMID11967536.S2CID195216803.
  11. ^Weitzel JN, Neuhausen SL, Adamson A, Tao S, Ricker C, Maoz A, et al. (August 2019)."Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer".Cancer.125(16): 2829–2836.doi:10.1002/cncr.32083.PMC7376605.PMID31206626.
  12. ^Wang Y, McKay JD, Rafnar T, Wang Z, Timofeeva MN, Broderick P, et al. (July 2014)."Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer".Nature Genetics.46(7): 736–41.doi:10.1038/ng.3002.PMC4074058.PMID24880342.
  13. ^Dai XX, Duan X, Liu HL, Cui XS, Kim NH, Sun SC (February 2014)."Chk2 regulates cell cycle progression during mouse oocyte maturation and early embryo development".Molecules and Cells.37(2): 126–32.doi:10.14348/molcells.2014.2259.PMC3935625.PMID24598997.
  14. ^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.
  15. ^Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC (January 2014)."Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway".Science.343(6170): 533–6.Bibcode:2014Sci...343..533B.doi:10.1126/science.1247671.PMC4048839.PMID24482479.
  16. ^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.Bibcode:2014PLoSO...989009S.doi:10.1371/journal.pone.0089009.PMC3923870.PMID24551207.
  17. ^Lee JS, Collins KM, Brown AL, Lee CH, Chung JH (March 2000). "hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response".Nature.404(6774): 201–4.Bibcode:2000Natur.404..201L.doi:10.1038/35004614.PMID10724175.S2CID4345911.
  18. ^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.
  19. ^Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER, Hurov KE, Luo J, et al. (May 2007). "ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage".Science.316(5828): 1160–6.Bibcode:2007Sci...316.1160M.doi:10.1126/science.1140321.PMID17525332.S2CID16648052.
  20. ^Lou Z, Minter-Dykhouse K, Wu X, Chen J (February 2003). "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways".Nature.421(6926): 957–61.Bibcode:2003Natur.421..957L.doi:10.1038/nature01447.PMID12607004.S2CID4411622.
  21. ^Adamson AW, Beardsley DI, Kim WJ, Gao Y, Baskaran R, Brown KD (March 2005)."Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2".Molecular Biology of the Cell.16(3): 1513–26.doi:10.1091/mbc.E04-02-0089.PMC551512.PMID15647386.
  22. ^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.
  23. ^Chen XB, Melchionna R, Denis CM, Gaillard PH, Blasina A, Van de Weyer I, et al. (November 2001)."Human Mus81-associated endonuclease cleaves Holliday junctions in vitro".Molecular Cell.8(5): 1117–27.doi:10.1016/s1097-2765(01)00375-6.PMID11741546.
  24. ^Tsvetkov L, Xu X, Li J, Stern DF (March 2003)."Polo-like kinase 1 and Chk2 interact and co-localize to centrosomes and the midbody".The Journal of Biological Chemistry.278(10): 8468–75.doi:10.1074/jbc.M211202200.PMID12493754.
  25. ^Bahassi EM, Conn CW, Myer DL, Hennigan RF, McGowan CH, Sanchez Y, Stambrook PJ (September 2002). "Mammalian Polo-like kinase 3 (Plk3) is a multifunctional protein involved in stress response pathways".Oncogene.21(43): 6633–40.doi:10.1038/sj.onc.1205850.PMID12242661.S2CID24106070.

Further reading

edit
edit

This article incorporates text from theUnited States National Library of Medicine,which is in thepublic domain.

Retrieved from "https://en.wikipedia.org/w/index.php?title=CHEK2&oldid=1248942316"