DNA replication and repairs

The role of some nutrients in metabolism is explained by their anti-oxidant influence on the molecular biological framework of the cell. This very useful series of reviews
In Nature 2007, vol 447, pp 923-958
give an insight into the systems which antioxidants might be protecting. A really good read.

Replication and protection of telomeres
R.E. Verdun SJ.Karlseder p 925-931
The ends of chromosomes need special protection against cellular processes that alter their genetic content It is essential to protect the chromosome ends to prevent triggering of the DNA-damage repair machinery and enzymatic attack.. These processes include digestion by enzymes, inappropriate repair by the DNA-damage repair machinery and the failure of DNA polymerases to replicate DNA strands completely. Protection is provided by telomeres. Telomeres are tightly regulated complexes consisting of repetitive G-rich DNA and specialized proteins Telomeres not only conceal linear chromosome ends from detection and inappropriate repair but also provide a buffer to counteract replication-associated shortening They are highly regulated and specialized and their structure and length contribute to chromosomes integrity .The review discusses how telomeres interact and cooperate with the DNA replication and DNA-damage repair machineries.

Expandable DNA repeats and human disease
S. M Mirkin p 932-940
Nearly 30 hereditary disorders in humans result from an increase in the number of copies of simple repeats in genomic DNA. These DNA repeats seem to be predisposed to such expansion because they have unusual structural features, which disrupt the cellular replication, repair and recombination machineries which affects gene coding or expression and leads to disease. The underlying disruption is that repeat-containing regions can form hairpins and other unusual structures when the DNA duplex separates. Repeat-associated diseases develop not only in response to the structural characteristics of repetitive DNA but also to those of the corresponding RNA. Many of these debilitating diseases result from repeat expansions in the non-coding regions of their resident genes.
Base-excision repair of oxidative DNA damage
S. S. David. V L. O’Shea & S. Kundu p 941-950
The specific pairing of DNA bases is crucial for the maintenance of genetic integrity. Bases are susceptible to oxidation by environmental agents and endogenous products, which modify the chemical structure and therefore the base-pairing properties of DNA
Base-excision repair has an important role in preventing mutations associated with a common product of oxidative damage to DNA, 8-oxoguani’ne. Recent structural studies have shown that 8-oxoguanine DNA glycosylases use an intricate series of steps to locate and excise 8-oxoguanine lesions efficiently against a high background of undamaged bases. The importance of preventing mutations associated with 8-oxoguanine is shown by a direct association between defects in the DNA glycosylase MUTYH and colorectal cancer. The properties of other guanine oxidation products and the associated DNA glycosylases that remove them are now also being revealed.

Chromatin dynamics and the preservation of genetic information
J A. Downs, M C. Nussenzweig and A Nussenzweig p 951-958
The genome is frequently damaged by double-strand breaks in the DNA. Changes in the cellular response to double-strand breaks are an important cause of cancer and other age-related pathologies. It is important to understand the enzymatic mechanisms involved in recognizing, signalling and repairing double-strand breaks. Chromatin has an important role in initiating, propagating and terminating this cellular response to DNA damage.
Genetic material in cells is organized into chromatin, which consists of DNA in association with histone proteins . This packaging makes damaged sites in the DNA relatively inaccessible to the repair machinery. The density of chromatin is reduced in the region of double-strand breaks, enabling access of DNA-damage sensor proteins to the lesion and initiation of repair. Much is known about how chromatin is ‘remodelled’ during gene transcription, and it is becoming evident that some of the same machinery is involved in the response to DNA damage.

Martin Eastwood
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