DNA damage - DNA-damage-induced responses

DNA-damage-induced responses

If the DNA damage is double-strand breaks (DSB) caused by ionizing radiation or radiomimetic agents, ataxia telangiectasia mutated serine-protein kinase (ATM) is activated [1]. If the DNA is damaged by UV light or UV-mimetic agents, ataxia telangiectasia and Rad3 related protein kinase (ATR) and DNA-activated protein kinase (DNA-PK) are activated [2]. ATM, ATR and DNA-PK belong to phosphoinositide-3-kinases family. These stimulated kinases signal the presence of DNA damage in mammalian cells by phosphorylating proteins that initiate cell-cycle arrest, apoptosis, and DNA repair [3], [4]. There are three basic pathways, which participate in DNA-damages-induced cell response.

Phosphorylation of the cell cycle checkpoint kinase 2 (Chk2) or cell cycle checkpoint kinase 1 (Chk1) [5] by ATM and/or ATR [6] are the initial steps in the checkpoint arrest [7]. Phosphorylated by phosphoinositide-3-kinases directly or indirectly, p53 [8] and Brca1 [9] participate in DNA-damage-induced cell cycle regulation (see maps 426. ATM/ATR regulation of G1/S checkpoint and 441. ATM/ATR regulation of G1/S checkpoint).

It is shown that DNA-damages-induced apoptosis is realized via the activated p53, Brca1, c-Abl and Chk2 (see map 542 DNA-damages-induced apoptosis) [10], [11], [12].

DNA repair is mediated mainly by Brca1 [13] (see map 427. Role of Brca1 and Brca2 in DNA Repair).

References:

1. Bakkenist CJ, Kastan MB
   DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003 Jan 30;421(6922):499-506
2. Dhanalakshmi S, Agarwal C, Singh RP, Agarwal R
   Silibinin up-regulates DNA-protein kinase-dependent p53 activation to enhance UVB-induced apoptosis in mouse epithelial JB6 cells. The Journal of biological chemistry 2005 May 27;280(21):20375-83
3. Dodson GE, Shi Y, Tibbetts RS
   DNA replication defects, spontaneous DNA damage, and ATM-dependent checkpoint activation in replication protein A-deficient cells. The Journal of biological chemistry 2004 Aug 6;279(32):34010-4
4. Yang J, Yu Y, Hamrick HE, Duerksen-Hughes PJ
   ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis 2003 Oct;24(10):1571-80
5. Zhao H, Watkins JL, Piwnica-Worms H
   Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Proceedings of the National Academy of Sciences of the United States of America 2002 Nov 12;99(23):14795-800
6. Cortez D, Guntuku S, Qin J, Elledge SJ
   ATR and ATRIP: partners in checkpoint signaling. Science (New York, N.Y.) 2001 Nov 23;294(5547):1713-6
7. Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S
   Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annual review of biochemistry 2004;73:39-85
8. Taylor WR, Stark GR
   Regulation of the G2/M transition by p53. Oncogene 2001 Apr 5;20(15):1803-15
9. Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA, Khanna KK
   BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage. The Journal of biological chemistry 2004 Jul 23;279(30):31251-8
10. Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C, Christians FC, Ellisen LW, Maheswaran S, Oliner JD, Haber DA
    Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 1999 May 28;97(5):575-86
11. Norbury CJ, Zhivotovsky B
    DNA damage-induced apoptosis. Oncogene 2004 Apr 12;23(16):2797-808
12. Sordet O, Khan QA, Kohn KW, Pommier Y
    Apoptosis induced by topoisomerase inhibitors. Current medicinal chemistry. Anti-cancer agents 2003 Jul;3(4):271-90
13. Yoshida K, Miki Y
    Role of BRCA1 and BRCA2 as regulators of DNA repair, transcription, and cell cycle in response to DNA damage. Cancer science 2004 Nov;95(11):866-71