Apoptosis and survival - DNA-damage-induced apoptosis

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DNA damage-induced apoptosis

Direct DNA damage by ionizing radiation or UV activates interconnected apoptotic pathways. In the case of double-strand breaks (DSB) caused by ionizing radiation or radiomimetic agents, ataxia telangiectasia mutated serine-protein kinase (ATM) gets activated [1]. If the DNA damage is caused 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 activate by phosphorylation different proteins in the apoptotic pathways [3], [4].

The activated ATM, ATR and DNA-PK rapidly phosphorylate histone H2AX. Shortly after the irradiation, H2AX forms discrete foci which consist of some mediators of DNA damage (including, for example, Nijmegen breakage syndrome 1 protein (nibrin)). Nibrin promotes activation of breast and ovarian cancer susceptibility protein 1 (BRCA1) directly [5] or indirectly via Fanconi anemia complementation group D2 protein, isoform 1 (FANCD2) [6]. FANCD2 is a link between the Fanconi anemia and ATM damage response pathways. FANCD2 is phosphorylated by ATM in response to ionizing radiation and is monoubiquitinated by Fanconi anemia complex (FANC complex). Active FANCD2 then interacts with BRCA1 and forms discrete nuclear foci [6].

ATR activates phosphorylation of BRCA1 directly [7] or indirectly via BLM [5].

The activated ATM, ATR and DNA-PK may phosphorylate p53 and E2F transcription factor 1 (E2F1) directly or indirectly via cell cycle checkpoint kinases (Chk1 and/or Chk2) [8], [9]. Cell cycle regulator RAD9 may participate in phosphorylation of Chk1 by ATM [10]. H2AX/nibrin or nibrin may participate in phosphorylation of Chk2 by ATM, ATR and DNA-PK [11].

E2F1, in turn, may activate of expression of Chk2 [8].

Stimulated ATM and DNA-PK activate by direct phosphorylation the proto-oncogene tyrosine-protein kinase c-Abl [12], [13].

The activated p53, E2F1, BRCA1, c-Abl and Rad 9 stimulate the further promotion of a signal on apoptotic pathways.

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. 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
  4. Norbury CJ, Zhivotovsky B
    DNA damage-induced apoptosis. Oncogene 2004 Apr 12;23(16):2797-808
  5. Davalos AR, Campisi J
    Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks. The Journal of cell biology 2003 Sep 29;162(7):1197-209
  6. Bogliolo M, Cabré O, Callén E, Castillo V, Creus A, Marcos R, Surrallés J
    The Fanconi anaemia genome stability and tumour suppressor network. Mutagenesis 2002 Nov;17(6):529-38
  7. Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT
    Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes & development 2000 Dec 1;14(23):2989-3002
  8. Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES, Johnson DG
    E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Molecular cancer research : MCR 2004 Apr;2(4):203-14
  9. Stevens C, Smith L, La Thangue NB
    Chk2 activates E2F-1 in response to DNA damage. Nature cell biology 2003 May;5(5):401-9
  10. Blankley RT, Lydall D
    A domain of Rad9 specifically required for activation of Chk1 in budding yeast. Journal of cell science 2004 Feb 1;117(Pt 4):601-8
  11. Lee JH, Xu B, Lee CH, Ahn JY, Song MS, Lee H, Canman CE, Lee JS, Kastan MB, Lim DS
    Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. Molecular cancer research : MCR 2003 Jul;1(9):674-81
  12. Takao N, Mori R, Kato H, Shinohara A, Yamamoto K
    c-Abl tyrosine kinase is not essential for ataxia telangiectasia mutated functions in chromosomal maintenance. The Journal of biological chemistry 2000 Jan 14;275(2):725-8
  13. 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

  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. 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
  4. Norbury CJ, Zhivotovsky B
    DNA damage-induced apoptosis. Oncogene 2004 Apr 12;23(16):2797-808
  5. Davalos AR, Campisi J
    Bloom syndrome cells undergo p53-dependent apoptosis and delayed assembly of BRCA1 and NBS1 repair complexes at stalled replication forks. The Journal of cell biology 2003 Sep 29;162(7):1197-209
  6. Bogliolo M, Cabré O, Callén E, Castillo V, Creus A, Marcos R, Surrallés J
    The Fanconi anaemia genome stability and tumour suppressor network. Mutagenesis 2002 Nov;17(6):529-38
  7. Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT
    Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes & development 2000 Dec 1;14(23):2989-3002
  8. Powers JT, Hong S, Mayhew CN, Rogers PM, Knudsen ES, Johnson DG
    E2F1 uses the ATM signaling pathway to induce p53 and Chk2 phosphorylation and apoptosis. Molecular cancer research : MCR 2004 Apr;2(4):203-14
  9. Stevens C, Smith L, La Thangue NB
    Chk2 activates E2F-1 in response to DNA damage. Nature cell biology 2003 May;5(5):401-9
  10. Blankley RT, Lydall D
    A domain of Rad9 specifically required for activation of Chk1 in budding yeast. Journal of cell science 2004 Feb 1;117(Pt 4):601-8
  11. Lee JH, Xu B, Lee CH, Ahn JY, Song MS, Lee H, Canman CE, Lee JS, Kastan MB, Lim DS
    Distinct functions of Nijmegen breakage syndrome in ataxia telangiectasia mutated-dependent responses to DNA damage. Molecular cancer research : MCR 2003 Jul;1(9):674-81
  12. Takao N, Mori R, Kato H, Shinohara A, Yamamoto K
    c-Abl tyrosine kinase is not essential for ataxia telangiectasia mutated functions in chromosomal maintenance. The Journal of biological chemistry 2000 Jan 14;275(2):725-8
  13. 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

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