CHEK2

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Checkpoint kinase 2
Protein CHEK2 PDB 1gxc.png
PDB rendering based on 1gxc[1].
Available structures
PDBOrtholog search: PDBe, RCSB
Identifiers
SymbolsCHEK2 ; CDS1; CHK2; HuCds1; LFS2; PP1425; RAD53; hCds1
External IDsOMIM604373 MGI1355321 HomoloGene38289 ChEMBL: 2527 GeneCards: CHEK2 Gene
EC number2.7.11.1
RNA expression pattern
PBB GE CHEK2 210416 s at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez1120050883
EnsemblENSG00000183765ENSMUSG00000029521
UniProtO96017Q9Z265
RefSeq (mRNA)NM_001005735NM_016681
RefSeq (protein)NP_001005735NP_057890
Location (UCSC)Chr 22:
29.08 – 29.14 Mb
Chr 5:
110.84 – 110.87 Mb
PubMed search[1][2]
 
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Checkpoint kinase 2
Protein CHEK2 PDB 1gxc.png
PDB rendering based on 1gxc[1].
Available structures
PDBOrtholog search: PDBe, RCSB
Identifiers
SymbolsCHEK2 ; CDS1; CHK2; HuCds1; LFS2; PP1425; RAD53; hCds1
External IDsOMIM604373 MGI1355321 HomoloGene38289 ChEMBL: 2527 GeneCards: CHEK2 Gene
EC number2.7.11.1
RNA expression pattern
PBB GE CHEK2 210416 s at tn.png
More reference expression data
Orthologs
SpeciesHumanMouse
Entrez1120050883
EnsemblENSG00000183765ENSMUSG00000029521
UniProtO96017Q9Z265
RefSeq (mRNA)NM_001005735NM_016681
RefSeq (protein)NP_001005735NP_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 CHK2 checkpoint homolog. It is located on the long (q) arm of chromosome 22.[2][3][4]

Function[edit]

The protein encoded by this gene, CHK2, is a protein kinase that is activated in response to DNA damage and is involved in cell cycle arrest.[2]

In response to DNA damage and replication blocks, cell cycle progression is halted through the control of 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.[5] In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage.[6][7]

Related conditions[edit]

A mutation in CHEK2 gene results in decreased DNA-repair, or inability of the cell to undergo apoptosis when it ought to have done so. Thus, a mutation leads to an increased susceptibility to cancer. The following conditions are examples of such cancers.

Breast cancer[edit]

A deletion-mutation at position 1100 of the CHEK2 gene is associated with an increased risk of breast cancer, particularly in the European population. In women of Northern and Eastern European descent CHEK2*1100delC carrier status confers a 2-3 fold risk of breast cancer. In this ethnic group, women with a familial history of breast cancer have a 4.8 fold risk of breast cancer equal to a lifetime risk of breast cancer of 37%.[8]

Li-Fraumeni syndrome[edit]

The CHEK2*1100delC mutation was originally associated with the Li-Fraumeni syndrome,[9] however the relative high prevalence of the mutation in the general population (0.5%) has made this association unlikely.[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.[6][18]

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 Matsuoka S, Huang M, Elledge SJ (December 1998). "Linkage of ATM to cell cycle regulation by the Chk2 protein kinase". Science 282 (5395): 1893–7. doi:10.1126/science.282.5395.1893. PMID 9836640. 
  3. ^ Blasina A, de Weyer IV, Laus MC, Luyten WH, Parker AE, McGowan CH (January 1999). "A human homologue of the checkpoint kinase Cds1 directly inhibits Cdc25 phosphatase". Curr. Biol. 9 (1): 1–10. doi:10.1016/S0960-9822(99)80041-4. PMID 9889122. 
  4. ^ Chaturvedi P, Eng WK, Zhu Y, Mattern MR, Mishra R, Hurle MR, Zhang X, Annan RS, Lu Q, Faucette LF, Scott GF, Li X, Carr SA, Johnson RK, Winkler JD, Zhou BB (July 1999). "Mammalian Chk2 is a downstream effector of the ATM-dependent DNA damage checkpoint pathway". Oncogene 18 (28): 4047–54. doi:10.1038/sj.onc.1202925. PMID 10435585. 
  5. ^ Chehab NH, Malikzay A, Appel M, Halazonetis TD (February 2000). "Chk2/hCds1 functions as a DNA damage checkpoint in G1 by stabilizing p53". Genes Dev. 14 (3): 278–88. doi:10.1101/gad.14.3.278. PMC 316357. PMID 10673500. 
  6. ^ a b 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. doi:10.1038/35004614. PMID 10724175. 
  7. ^ "Entrez Gene: CHEK2 CHK2 checkpoint homolog (S. pombe)". 
  8. ^ Meijers-Heijboer H, van den Ouweland A, Klijn J, et al. (May 2002). "Low-penetrance susceptibility to breast cancer due to CHEK2(*)1100delC in noncarriers of BRCA1 or BRCA2 mutations". Nat. Genet. 31 (1): 55–9. doi:10.1038/ng879. PMID 11967536. 
  9. ^ Bell DW, Varley JM, Szydlo TE, Kang DH, Wahrer DC, Shannon KE, Lubratovich M, Verselis SJ, Isselbacher KJ, Fraumeni JF, Birch JM, Li FP, Garber JE, Haber DA (December 1999). "Heterozygous germ line hCHK2 mutations in Li-Fraumeni syndrome". Science 286 (5449): 2528–31. doi:10.1126/science.286.5449.2528. PMID 10617473. 
  10. ^ Evans DG, Birch JM, Narod SA (January 2008). "Is CHEK2 a cause of the Li-Fraumeni syndrome?". J. Med. Genet. 45 (1): 63–4. doi:10.1136/jmg.2007.054700. PMID 18178638. 
  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. ^ 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.