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 . 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 . ATM,
ATR and DNA-PK belong to
phosphoinositide-3-kinases family. These stimulated kinases activate by phosphorylation
different proteins in the apoptotic pathways , .
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  or indirectly via Fanconi
anemia complementation group D2 protein, isoform 1 (FANCD2)
. 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 .
ATR activates phosphorylation of
BRCA1 directly  or indirectly via
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)
, . Cell cycle regulator RAD9
may participate in phosphorylation of Chk1
by ATM .
nibrin may participate in phosphorylation of
Chk2 by ATM, ATR
and DNA-PK .
E2F1, in turn, may activate
of expression of Chk2 .
Stimulated ATM and DNA-PK
activate by direct phosphorylation the proto-oncogene tyrosine-protein
kinase c-Abl , .
The activated p53, E2F1, BRCA1, c-Abl
and Rad 9 stimulate the further promotion of
a signal on apoptotic pathways.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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