Chk2 Review

The p53 tumor-suppressor gene integrates numerous signals that control cell life and death. Several novel molecules involved in p53 signaling, including Chk2 (1), p53R2 (2), p53AIP1 (3), Noxa (4), PIDD (5), and PID/MTA2 (6), were recently discovered. The checkpoint kinase Chk2 is the mammalian homologue of yeast Cds1/Rad53. In response to DNA damage, the checkpoint kinase ATM phosphorylates and activates Chk2, which in turn directly phosphorylates and activates p53 (7,8). Chk2 serves as ATM downstream effector to mediate activation of p53. Chk2 also phosphorylates and activates BRCA1, the product of a tumor suppressor gene that is mutated in breast and ovarian cancer (9).

1. Matsuoka S, Huang M, Elledge SJ. Linkage of ATM to cell cycle regulation by the Chk2 protein kinase. Science. 1998;282:1893-7.
2. Tanaka H, Arakawa H, Yamaguchi T, Shiraishi K, Fukuda S, Matsui K, Takei Y, Nakamura Y. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature. 2000;404:42-9.
3. Oda E, Ohki R, Murasawa H, Nemoto J, Shibue T, Yamashita T, Tokino T, Taniguchi T,
4. Oda K, Arakawa H, Tanaka T, Matsuda K, Tanikawa C, Mori T, Nishimori H, Tamai K, Tokino T, Nakamura Y, Taya Y. p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53. Cell. 2000 Sep 15;102(6):849-62.
5. Luo J, Su F, Chen D, Shiloh A, Gu W. Deacetylation of p53 modulates its effect on cell growth and apoptosis. Nature. 2000;408:377-81.
6. Lin Y, Ma W, Benchimol S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat Genet. 2000;26:122-7.
7. Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro.Proc Natl Acad Sci USA. 2000 ;97:10389-94.
8. Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW. DNA damage-induced activation of p53 by the checkpoint kinase Chk2. Science. 2000;287:1824-7
9. Lee JS, Collins KM, Brown AL, Lee CH, Chung JH. hCds1-mediated phosphorylation of BRCA1 regulates the DNA damage response. Nature. 2000;404:201-4.