The DNA damage response: Balancing the scale between cancer and ageing

Abstract

Defects in the DNA damage response often lead to an increased susceptibility to cancer, and so the DDR presents an interesting set of novel therapeutic targets. The maintenance of genomic integrity by the DDR has also been found to be involved in the process of organismal ageing. While the removal of cells containing damaged DNA can be beneficial in the prevention of cancer, it may contribute to both normal and pathological ageing.

Figure 1.

The action of the key DDR components following DNA damage. Following SSBs, RPA is recruit-ed to the ssDNA along with the 9-1-1 complex. This in turn recruits the ATR-ATRIP complex, allowing ATR to phosphorylate and activate its downstream substrates. Damage that results in DSBs causes the recruitment of the MRN complex, which binds and activates ATM. The pathways at least partially con-verge on BRIT1, which regulates the expression of BRCA1. The BRCA1-BARD1 complex in turn regulates the phosphorylation state of p53.

Figure 2.

The downstream effectors of the DDR. After activation by ATR, Chk1 phosphorylates the CDC25 family of phosphatases, thereby targeting them for ubiquityn-ation and subsequent degradation and preventing the activation of cyclin-dependent kinases. Chk2 is activated by ATM and phosphorylates p53, causing its stabilization and activation, while ATM also activates p53 directly. This in turn regulates the expression of the CDK inhibitor p21, leading to arrest of the cell cycle.

Figure 3.

The role of p53 in senescence. The determination of cell fate following p21-induced cell cycle arrest is dependent on the activity of p53 towards mTOR. Under conditions where p53 can inhibit mTOR via the transcriptional activation of specific target genes, cells will enter quiescence. However, when p53 cannot inhibit mTOR, cells will become senescent. The transcriptional activity of p53, and so its activity towards mTOR, can also be regulated by post-translational modifications such as acetylation, which is linked to the activity of the DDR.