Structure and function of the components of the human DNA mismatch repair system

Abstract

DNA mismatch repair (MMR) is one of the several enzyme systems involved in DNA homeostasis. DNA MMR is involved in the repair of specific types of errors that occur during new DNA synthesis; loss of this system leads to an accelerated accumulation of potential mutations, and predisposes to certain types of cancers. Germline mutations in some of the DNA MMR genes cause the hereditary cancer predisposition, Lynch syndrome. This review addresses advances in the biochemistry of DNA MMR and its relationship to carcinogenesis. ' 2006 Wiley-Liss, Inc.Key words: DNA mismatch repair; microsatellite instability; lynch syndrome; HNPCC; colorectal cancer; hMSH2; hMLH1; hMSH6; hPMS2; exonuclease IThe DNA mismatch repair (MMR) system was at one time in the exclusive domain of the microbial biochemist, but has been thrust into the mainstream of the cancer biologist because of its importance in carcinogenesis. Approximately 15% of colorectal cancers develop through mechanisms whereby this form of DNA maintenance is lost, leading to 100-to 1,000-fold increases in error rates during replication. This review of recent progress in DNA MMR research is intended for the tumor biologist who is interested in structural and functional details of this system. There have been several reviews of the clinical aspects of DNA MMR that emphasize the diagnostic uses of testing for microsatellite instability and the use of immunohistochemistry of the DNA MMR proteins in colorectal cancer. [1][2][3][4][5][6][7] This review will serve to complement those reviews, and will highlight some of the biochemical issues that underlie DNA MMR. Components of the DNA MMR systemThe DNA MMR system corrects DNA base pairing errors in newly replicated DNA. The primary DNA polymerase in eukaryotic S phase DNA replication, polymerase d, has 3 0 > 5 0 proofreading activity that corrects 99% of replication errors. Nevertheless, mispaired nucleotides are occasionally left behind, as are small insertion/deletion mutations that are prone to occur at repetitive sequences. Microsatellites are multiple tandem repeats in which the repetitive element consists of a short number of nucleotides (perhaps 6 or fewer, and for functional studies, usually 1-4), and these are particularly prone to slippage and inefficient proofreading by DNA polymerase. The MMR system is critical to correct these problems, and if inactivated, the resulting shortening of microsatellites is a telltale sign of the ensuing ''microsatellite instability'' (MSI) phenotype. MSI testing is most often performed on mononucleotide or dinucleotide repeats.A casual description of the MMR system would state that the MMR system is chiefly a sensory system that scans DNA, and when a nucleotide mispair is detected, removes the error and summons DNA polymerase to repeat the synthesis, and this time corrects the error. This works because even in repetitive sequences, the error rate of DNA polymerase is low, and so simply having a second chance usually fixes the problem.More formally, the MMR system is an excision/resynt...

Molecular signaling mechanisms of apoptosis in hereditary non-polyposis colorectal cancer

“…The DNA mismatch repair system is considered as sensory system that can scan DNA, and when there is any insertion, deletion, or mispaired nucleotide, this system is able to detect and remove the errors [38] . DNA mismatch repair system can be divided into four phases: first recognition of mismatch base by MutS, second recruitment of MutL, third removal of incorrect base, fourth re-synthesis of corrected DNA by DNA polymerase enzyme using the parent strand as a template [39] .…”

“…MSH proteins have ATPase activity, one adenosine triphosphate (ATP) binding site present at each molecule [41] . In the presence of adenosine diphosphate (ADP) MutS protein will bind tightly to the mismatches on the DNA strand, while in the presence of ATP the MutS will act as sliding clamp [38] . MutS protein will move along to the DNA to identify which strand needs to be repaired.…”

“…MutS protein will move along to the DNA to identify which strand needs to be repaired. It has been proposed that the feature of the newly synthesized strand is a single strand nick for example the gaps between Okazaki fragments in the lagging strand [38] . So MMR will excise the strand containing a nick, which needs exonuclease activity.…”

“…MutL binds to the complex and interact with MutS at the site of the mismatches. MutL protein will transfer DNA polymerase, PCNA, and recruit exonuclease Ⅰ for excision up to kilobase of DNA [38] . Excision of the mismatches can be either 5' to 3' or the opposite.…”

Impact of DNA mismatch repair system alterations on human fertility and related treatments

“…Consequently, there are multiple mechanisms to repair DNA damage and maintain the stability of the DNA sequence in all tissues and cells. One of them, known as DNA mismatch repair (MMR), mainly repairs base-pair mismatches and insertion/deletion loops (IDLs) (Jascur and Boland, 2006). MMR repairs DNA mismatches arising during replication, thereby preventing deleterious mutations and maintaining genomic stability.…”