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.
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DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation.
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