Pathway Map Details

DNA damage_DNA-damage-induced responses

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ATR, ATM, c-Abl, NFBD1, Chk1, p53, Chk2, DNA-PK, Brca1


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 ).


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  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
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  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