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Science 24 December 1999:
Vol. 286. no. 5449, pp. 2528 - 2531
DOI: 10.1126/science.286.5449.2528
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Reports

Heterozygous Germ Line hCHK2 Mutations in Li-Fraumeni Syndrome

Daphne W. Bell, 1 Jennifer M. Varley, 2 Tara E. Szydlo, 1* Deborah H. Kang, 1* Doke C. R. Wahrer, 1* Kristen E. Shannon, 1 Marcie Lubratovich, 1 Sigitas J. Verselis, 3 Kurt J. Isselbacher, 1 Joseph F. Fraumeni, 4 Jillian M. Birch, 5 Frederick P. Li, 3 Judy E. Garber, 3 Daniel A. Haber 1dagger

The hCHK2 gene encodes the human homolog of the yeast Cds1 and Rad53 G2 checkpoint kinases, whose activation in response to DNA damage prevents cellular entry into mitosis. Here, it is shown that heterozygous germ line mutations in hCHK2 occur in Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in the TP53 gene. These observations suggest that hCHK2 is a tumor suppressor gene conferring predisposition to sarcoma, breast cancer, and brain tumors, and they also provide a link between the central role of p53 inactivation in human cancer and the well-defined G2 checkpoint in yeast.

1 Massachusetts General Hospital Center for Cancer Risk Analysis and Harvard Medical School, Building 149, Charlestown, MA 02129, USA.
2 Cancer Research Campaign Department of Cancer Genetics, Paterson Institute for Cancer Research, Manchester M20 4BX, UK.
3 Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02114, USA.
4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
5 Cancer Research Campaign Paediatric and Familial Cancer Research Group, Royal Manchester Children's Hospital, Manchester M27 1HA, UK.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: Haber{at}helix.mgh.harvard.edu

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L. Tsvetkov, X. Xu, J. Li, and D. F. Stern (2003)
J. Biol. Chem. 278, 8468-8475
   Abstract »    Full Text »    PDF »
NFBD1/KIAA0170 Is a Chromatin-associated Protein Involved in DNA Damage Signaling Pathways.
X. Xu and D. F. Stern (2003)
J. Biol. Chem. 278, 8795-8803
   Abstract »    Full Text »    PDF »
Direct Kinase-to-Kinase Signaling Mediated by the FHA Phosphoprotein Recognition Domain of the Dun1 DNA Damage Checkpoint Kinase.
V. I. Bashkirov, E. V. Bashkirova, E. Haghnazari, and W.-D. Heyer (2003)
Mol. Cell. Biol. 23, 1441-1452
   Abstract »    Full Text »    PDF »
CHK2-decreased protein expression and infrequent genetic alterations mainly occur in aggressive types of non-Hodgkin lymphomas.
F. Tort, S. Hernandez, S. Bea, A. Martinez, M. Esteller, J. G. Herman, X. Puig, E. Camacho, M. Sanchez, I. Nayach, et al. (2002)
Blood 100, 4602-4608
   Abstract »    Full Text »    PDF »
p53 Serine 392 Phosphorylation Increases after UV through Induction of the Assembly of the CK2{middle dot}hSPT16{middle dot}SSRP1 Complex.
D. M. Keller and H. Lu (2002)
J. Biol. Chem. 277, 50206-50213
   Abstract »    Full Text »    PDF »
Low rate of TP53 germline mutations in breast cancer/sarcoma families not fulfilling classical criteria for Li-Fraumeni syndrome.
D G R Evans, J M Birch, M Thorneycroft, G McGown, F Lalloo, and J M Varley (2002)
J. Med. Genet. 39, 941-944
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Evidence for a Hereditary Neuroblastoma Predisposition Locus at Chromosome 16p12-13.
J. M. Maris, M. J. Weiss, Y. Mosse, G. Hii, C. Guo, P. S. White, M. D. Hogarty, T. Mirensky, G. M. Brodeur, T. R. Rebbeck, et al. (2002)
Cancer Res. 62, 6651-6658
   Abstract »    Full Text »    PDF »
Chk2 Is a Tumor Suppressor That Regulates Apoptosis in both an Ataxia Telangiectasia Mutated (ATM)-Dependent and an ATM-Independent Manner.
A. Hirao, A. Cheung, G. Duncan, P.-M. Girard, A. J. Elia, A. Wakeham, H. Okada, T. Sarkissian, J. A. Wong, T. Sakai, et al. (2002)
Mol. Cell. Biol. 22, 6521-6532
   Abstract »    Full Text »    PDF »
Interfaces Between the Detection, Signaling, and Repair of DNA Damage.
J. Rouse and S. P. Jackson (2002)
Science 297, 547-551
   Abstract »    Full Text »    PDF »
Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response.
M. T. Jack, R. A. Woo, A. Hirao, A. Cheung, T. W. Mak, and P. W. K. Lee (2002)
PNAS 99, 9825-9829
   Abstract »    Full Text »    PDF »
Chk2 Activation and Phosphorylation-Dependent Oligomerization.
X. Xu, L. M. Tsvetkov, and D. F. Stern (2002)
Mol. Cell. Biol. 22, 4419-4432
   Abstract »    Full Text »    PDF »
Posttranscriptional Regulation of the RAD5 DNA Repair Gene by the Dun1 Kinase and the Pan2-Pan3 Poly(A)-Nuclease Complex Contributes to Survival of Replication Blocks.
A. Hammet, B. L. Pike, and J. Heierhorst (2002)
J. Biol. Chem. 277, 22469-22474
   Abstract »    Full Text »    PDF »
A single unbranched S-phase DNA damage and replication fork blockage checkpoint pathway.
M. A. Marchetti, S. Kumar, E. Hartsuiker, M. Maftahi, A. M. Carr, G. A. Freyer, W. C. Burhans, and J. A. Huberman (2002)
PNAS 99, 7472-7477
   Abstract »    Full Text »    PDF »
Phosphorylation of Threonine 68 Promotes Oligomerization and Autophosphorylation of the Chk2 Protein Kinase via the Forkhead-associated Domain.
J.-Y. Ahn, X. Li, H. L. Davis, and C. E. Canman (2002)
J. Biol. Chem. 277, 19389-19395
   Abstract »    Full Text »    PDF »


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