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genome integrity

Wednesday 17 September 2003

Maintaining the integrity of genetic information is fundamental for the life of a cell and the survival of a species. Cells can encounter DNA damage as a consequence of normal cellular metabolism or as a result of exposure to chemical or physical agents.

Eukaryotic cells have developed a network of responses in order to deal with DNA damage thereby preserving the integrity of their genetic information.

In the presence of extensive genetic insult, a surveillance mechanism or "checkpoint" is activated. The activation of this signal transduction pathway leads to an arrest of cell cycle progression to prevent replication and segregation of damaged DNA molecules and to induce transcription of several repair genes. Existing repair mechanisms are also mobilised, in a coordinated effort to restore the original DNA structure.

Genes involved in either cell cycle checkpoints, DNA repair or genes that maintain the fidelity of chromosome segregation are often termed "antimutators" or "caretaker" genes, because they control the stability of the genome and prevent accumulation of mutations in so-called "gatekeeper" genes. This latter group of genes directly regulate the growth of tumours either by inhibiting growth or promoting death.

A fundamental requirement for many DNA metabolism processes is the separation of the complementary strands of the DNA duplex. This is promoted by DNA helicases, which unwind nucleic-acid duplexes in an ATP-dependent manner to provide access to the template for proteins of the replication, recombination, repair and transcription machineries.

Multiple DNA helicase families have been identified, all containing seven hallmark helicase motifs; members within each helicase family also share sequence homologies beyond and between these motifs.

One example is the RecQ helicase family, named after the RecQ protein of Escherichia coli, which was identified during a search for mutants sensitive to thymine starvation.

Five members of the RecQ family have been identified in the human genome, and mutations in three of the genes are responsible for genetic diseases that are characterised by genomic instability and a high incidence of cancer.

Because mutants in RecQ family genes in other species also have unstable chromosomes, it was proposed that members of the RecQ helicase family play a central role in the maintenance of genomic stability and thereby the prevention of tumorigenesis.

Pathology

Caretaker tumour suppressor genes and genome integrity

In contrast to gatekeepers tumour suppressor genes, caretaker tumour suppressor genes genes do not directly regulate proliferation, but act to prevent genomic instability.

Thus, mutation of caretaker genes leads to accelerated conversion of a normal cell to a neoplastic cell.

Many caretaker genes are required for the maintenance of genome integrity. Caretaker genes play a role, directly or indirectly, in the repair of DNA strand breaks by the homologous recombination pathway, and that are associated with cancer-prone clinical syndromes, in particular ataxia telangiectasia, hereditary breast cancer, Bloom’s syndrome and Werner’s syndrome.

- ataxia telangiectasia
- hereditary breast cancer
- Bloom’s syndrome

- mutations of RecQ helicases

  • Werner’s syndrome

References

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

- Levitt NC, Hickson ID. Caretaker tumour suppressor genes that defend genome integrity. Trends Mol Med. 2002 Apr;8(4):179-86. PMID: #11927276#