The genetic material of our cells is constantly under attack from intrinsic and extrinsic agents which cause DNA damage. Although the repair of different types of DNA lesion relies on different sets of proteins, the various forms of DNA damage trigger common signal transduction pathways that orchestrate a series of events referred to as the "DNA damage response".
This involves slowing or arrest of cell cycle progression in order to delay key cell cycle transitions until repair has occurred, changes in chromatin structure at the site of DNA damage and modulation of various proteins involved in DNA repair.
Defects in the DNA damage response lead to genomic instability, cancer predisposition, immune disorders, neurodegeneration and often cause lethality, underlying the importance of this response in organism physiology.
DNA-damage signalling pathways
Following exposure to ionizing radiation (IR) or ultraviolet (UV) light, the induction of DNA-damage signalling pathways is triggered by different mechanisms.
Among many types of base lesions, ionizing radiation induces DNA strand breaks that, through chromatin alterations, are thought to trigger the activation of the ataxia telangiectasia mutated (ATM) kinase, leading to the induction of the p53 response (TP53).
By contrast, induction of the DNA-damage signalling pathway following UV-light irradiation seems to be triggered by blockage of either transcription or replication.
The ataxia telangiectasia and Rad3 related (ATR) kinase has been indicated to be a sensor of replication blockage and might have a similar role in sensing blocked transcription complexes, although evidence for this is still lacking.
SMG1 is a newly discovered member of the DNA-damage-inducible phosphatidylinositol-3-kinase-related kinase family, which also includes ATM, ATR and DNA-dependent protein kinase (DNAPK). The SMG1 kinase might respond to both DNA damage and truncated mRNA species that might arise as a result of blocked transcription.
All of these protein kinases can directly phosphorylate p53 at the serine-15 site, a modification that is thought to stimulate further protein modifications, leading to the activation and stabilization of the p53 protein.
In addition to the phosphorylation of p53, ATM and ATR phosphorylate some common and some unique substrates, ultimately resulting in the activation of pathways dictating the fate of the cell, such as DNA repair, cell-cycle checkpoints or apoptosis.
Pathways
| ATM | BRCA1 | CHEK2 |
Features
ionizing radiation-induced DNA damage signaling
References
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