Replication on a damaged template

Mutations caused by chemicals are mostly due to errors of DNA replication on a damaged template. Repair therefore is critical as if this occurs efficiently and before replication,... 

It now seems certain that mammalian cells also possess varying capacities to replicate their DNA on a template containing unexcised damage. It is also apparent, however, that the mechanism of any such repair process differs from that which is thought to occur in bacteria. However, irrespective of the mechanism involved in synthesising past radiation or chemically-induced lesions in DNA, it has been found that in some cells the process is amenable to inhibition by the trimethylxanthine, caffeine. Thus it has been shown that the rate of elongation of newly synthesised DNA in UV-irradiated or chemically-treated cells, was dramatically impaired in the presence of caffeine. 

Chapter 22 describes how different chemical agents react with DNA and form interstrand crosslinks (ICLs) that covalently link the two strands together. This poses a special problem for the cell in that the replication and transcription machineries are unable to progress or unwind the helix at the sites where the two strands are covalently linked to each other. It also presents a challenge for DNA repair since the damaged sites occur in close proximity to each other on opposing strands. Hence it is difficult for one strand to serve as a template for repair of the other strand because they both contain damaged DNA. 

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