Pathway Map Details
DNA damage_DNA-damage-induced responses
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Object list (links open in MetaCore):
ATR, ATM, c-Abl, NFBD1, Chk1, p53, Chk2, DNA-PK, Brca1
Description:
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:
- Bakkenist CJ, Kastan MB
DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003 Jan 30;421(6922):499-506 - 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 - 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 - 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 - 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 - Cortez D, Guntuku S, Qin J, Elledge SJ
ATR and ATRIP: partners in checkpoint signaling. Science 2001 Nov 23;294(5547):1713-6 - 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 - Taylor WR, Stark GR
Regulation of the G2/M transition by p53. Oncogene 2001 Apr 5;20(15):1803-15 - 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 - 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 - Norbury CJ, Zhivotovsky B
DNA damage-induced apoptosis. Oncogene 2004 Apr 12;23(16):2797-808 - 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 - 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