Sensing of DNA Damage
Several genes are involved in the response to ionising radiation. The actual genes involved depend on the damage inflicted as well as the stage in the cell cycle. For instance, ATM is active in S phase whereas ATR is active in G2 phase.
MRN Complex (MRE11A, RAD50, NBN)
This set of three proteins form a complex that seems able to detect double strand breaks in DNA. Whether it or ATM (below) is responsible for the initial response to DNA damage is unclear. MRN complex is also involved in homologous recombination.
XRCC5 and XRCC6
Also known as Ku-80 and Ku-70, XRCC5/6 form a heterodimer that binds to free ends of DNA in the event of a double strand break. They are involved in the recruitment of PRKDC to the site and also in non-homologous end joining.
ATM and ATR
Ataxia-telangiectasia mutated (ATM) is the gene responsible for the ataxia-telangiectasia syndrome. It is a large protein that is activated in the presence of double-strand DNA breaks, in association with the MRN complex of proteins.
When activated, ATM phosphorylates a number of downstream proteins designed to recruit DNA repair genes to the break as well as signal the cell that DNA damage has occurred. The latter is accomplished by phosphorylation of TP53 (activating it) as well as MDM2 (preventing its binding to TP53). This leads to cell cycle arrest and increased expression of DNA repair genes. If the damage is unable to be repaired, TP53 also promotes apoptosis. Cell cycle arrest is also accomplished by the phosphorylation of the CHEK2 protein, which inhibits cyclin activity and prevents cell cycle progression.
DNA repair genes include BRCA1 and 2, RAD51, the MRN complex and DNA polymerases. Without ATM, these genes are unable to localise to the site of damage.
Ataxia-telangiectasia and Rad3 related gene (ATR) has a similar structure and function to ATM but is mostly active in G2. It phosphorylates CHEK1 instead of CHEK2 but otherwise functions in a similar fashion. ATR is also involved in single strand break sensing.
Protein Kinase, DNA Activated, Catalytic Polypeptide (PRKDC)
PRKDC, also known as DNA-PK, is another protein that responds to double strand breaks with the assistance of XRCC5 and XRCC6. It is involved in non-homologous end joining (NHEJ) of double strand breaks.
Transducers of the DNA Damage Response
TP53 and MDM2 are both targets of PRKDC and ATM/ATR. TP53 promotes cell cycle arrest and activation of cell cycle repair pathways. The major activator for cell cycle control is CDKN1A (or p21), which binds to CDK2 and CDK4 to prevent progression through the cell cycle.
CHEK2/CHEK1 are the other method of arresting the cell cycle. They inhibit the function of cdc25 which is important in the S and G2 phases of the cell cycle.
