Apoptosis and survival - DNA-damage-induced apoptosis

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:

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