How cell division is blocked by DNA damage?

When DNA is damaged for example by X-rays, protein kinases are activated and recruited to the site of damage. They in turn initiate a signaling cascade that causes arrest of the cell cycle. The first kinase at the site of damage is either ATM (Ataxia telangiectasia mutated) or ATR (Ataxia telangiectasia and Rad3 related) which recruits Chk1 and Chk 2 kinases at the same site. These kinases cause phosphorylation of the gene regulatory protein p53. Phosphorylation of p53 blocks Mdm2. Mdm2 is responsible for p53 ubiquitinylation and its proteosomal degradation. Thus blocking Mdm2 keeps p53 activity intact causing high level p53 accumulation. p53 then leads to transcription of CKI protein p21. The p21 binds and inactivates G1/S-Cdk and S-Cdk arresting the cell cycle at G1.

 

Interesting facts:

• Two families of genes, the cip/kip family (CDK interacting protein/Kinase inhibitory protein) and the INK4a/ARF (Inhibitor of Kinase 4/Alternative Reading Frame) prevent the progression of the cell cycle. Because these genes are instrumental in prevention of tumor formation, they are known as tumor suppressors.
• Synthetic inhibitors of Cdc25 could also be useful for the arrest of cell cycle and therefore be useful as antineoplastic and anticancer agents.
• A semi-autonomous transcriptional network acts in concert with the CDK-cyclin machinery to regulate the cell cycle.  

 

Further reading:

1. Alberts B, Johnson A, Lewis J,   et al.   2008.   Molecular Biology of the Cell   (5th ed.). Garland Science.   USA.
2. Karp G. 2010. Cell and Molecular Biology: Concepts and Experiments, John Wiley & Sons, Inc. USA.
3. Cooper G M, Hausman R E. 2007. The Cell: A Molecular Approach (4 th ed.). ASM Press,Washington, D.C.