Year: 2009
Type: article
Abstract: Defective MMR is also associated with 10% to 15% of sporadic colorectal cancers exhibiting MSI (Kinzler and Vogelstein, 1996;Kuismanen et al., 2000;Lynch and de la Chapelle, 2003;Veigl et al., 1998).Sporadic colorectal cancer with MSI but no detectable mutation in the MMR genes has frequently been shown to have promoter hypermethylation leading to gene silencing (mostly hMLH1 and in some cases hMSH6) (Peltomaki, 2001).This evidence suggests that while specific mutation of a MMR gene may not always be involved with MSI, an impaired MMR system is strongly linked to the MSI+ phenotype.Unrepaired mutations in DNA have been implicated in degenerative processes such as genetic disorders, carcinogenesis and aging (Jackson and Loeb, 1998;Kirkwood, 1989).Mutations are caused by myriads of endogenous and exogenous DNA damaging agents.However, a small fraction of genomic mutations is believed to result from replication errors, due to an intrinsic, very low inaccuracy of replicative DNA polymerases duplicating an undamaged parental DNA template.To fully appreciate the opportunities for generating errors during replication of the 6 x 10 9 -nucleotide human genome, one should consider various complex factors involved in the replication such as correct nucleotide selection by the replicative polymerase, proofreading mechanisms that include excision of misincorporated nucleotides, accuracy of associated accessory proteins and, last but not least, postreplication controls performed by a specialized repair process known as DNA mismatch repair.The largest numbers of mutations are thought to arise during replication as a consequence of damage to the parental DNA template.
Author: Saravanan Kaliyaperumal
Institution: University of Toledo
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W2167942834