genomic stability

A fundamental axiom of genetic inheritance is a requirement for exceptional genetic stability over many generations of cells and organisms. However, cells have to contend with both intracellular and extracellular environments that constantly challenge the chemical stability of the genome.

Additionally, although normal metabolic transactions of DNA such as replication, recombination and repair are generally highly accurate, there are limits to the fidelity of these processes, so genomic instability is promoted.

Classical Darwinian evolution is, of course, strictly dependent on the many sources of genetic variability that arise in populations of germ cells, so the notion of ’exceptional genetic stability’ is relative.

Life requires a finely tuned balance between the avoidance of mutations by DNA repair and other cellular responses to DNA damage that affect genetic stability, and the generation and persistence of mutations.

Genetic diversity in the germ line is essential to allow selection of genetic fitness, based on Darwinian evolution.

But mutations in the germ line afford the attendant risk of hereditary diseases or, in the case of recessive mutations, predisposition to such diseases. Mutations in somatic cells can have numerous phenotypic consequences, of which cancer is perhaps the most serious.

p53 and genomic stability

Mutations in TP53, encoding p53, which has been dubbed the ‘guardian of the genome’, are seen in >50% of all sporadic cancers in humans. p53 functions in a highly dynamic and controlled manner; induction of p53 leads to cell cycle arrest in G1 and/or G2, allowing time for DNA repair to take place, but may additionally lead to apoptotic cell death. Moreover, the loss of p53 results in genomic instability.

References

 Kapoor TM. Chromosome segregation: correcting improper attachment. Curr Biol. 2004 Dec 14;14(23):R1011-3. PMID: 15589138

 Draviam VM, Xie S, Sorger PK. Chromosome segregation and genomic stability. Curr Opin Genet Dev. 2004 Apr;14(2):120-5. PMID: 15196457