DNA repair defects in colon cancer

doi:10.1016/S0959-437X(03)00004-2

Current Opinion in Genetics & Development

Volume 13, Issue 1, February 2003, Pages 61-69

https://doi.org/10.1016/S0959-437X(03)00004-2 Get rights and content

Abstract

Defects in DNA-repair pathways lead to an accumulation of mutations in genomic DNA that result from non-repair or mis-repair of modifications introduced into the DNA by endogenous or exogenous agents or by the malfunction of DNA metabolic pathways. Until recently, only two repair pathways, postreplicative mismatch repair and nucleotide excision repair, have been linked to cancer in mammals, but these have been joined in recent months also by the damage-reversal and base-excision-repair processes, which have been shown to be inactivated, either through mutation or epigenetically, in human cancer.

Introduction

The genomic DNA of all organisms is constantly modified by exogenous and endogenous reagents [1]. In addition, some pathways of DNA metabolism such as DNA replication also modify the genetic material by introducing errors into newly synthesized strands. In order for the DNA to fulfil its role as a template for transcription, or to serve as the genetic blueprint that is passed onto the next generation, the cells of all organisms have evolved highly sophisticated and efficient machineries that maintain the integrity of their genomes. It could logically be anticipated that the malfunction of any repair pathway, be it damage reversal, base excision repair (BER), nucleotide excision repair, mismatch repair (MMR) or recombination repair [1], would lead to an increased frequency of mutations and thus to cancer in mammals. However, this does not appear to be the case: only a few genes that encode DNA repair enzymes have been shown to be mutated in human malignancies to date.

Malfunction of MMR in humans was first identified in 1993, in tumors of the colon, endometrium, ovary and other organs targeted by the hereditary non-polyposis colon cancer syndrome (HNPCC) (see 2., 3., 4., 5., 6. for recent reviews). Since that time microsatellite instability (MSI), the hallmark of MMR deficiency, has also been detected in many sporadic colon tumors, where it appears to be linked to a transcriptional silencing of the hMLH1 (where MLH stands for MutL homologue) gene [7]. The reasons underlying the tissue tropism of MMR malfunction are unclear. The principal task of MMR is to remove nucleotides that have been misincorporated into the newly synthesized strand by the replicative DNA polymerase and that have escaped detection by the proofreading activity of this enzyme complex. However, the MMR system also appears to be involved in post-replicative DNA-damage signaling, and it is this role that might help explain why the transformation process linked with MMR defects preferentially affects cells of rapidly proliferating tissues such as the colonic epithelium. This topic will be the major subject of discussion in the following paragraphs.

Recently, two more DNA repair enzymes have been implicated in colon cancer in humans. First, the gene encoding methylguanine methyl transferase (MGMT), a protein that removes methyl and other small alkyl groups from the O⁶-position of guanine (reviewed in [8]), has been shown to be transcriptionally silenced in some colon tumors (reviewed in [9]). The second example is MutY homologue (MYH) [10], a homologue of the E. coli MutY gene, which encodes a DNA-glycosylase responsible for the removal from DNA of adenines mispaired with 8-oxoguanine (G°). MYH mutations have been identified in patients with multiple colorectal adenoma syndrome 11.••, 12.••. Most recently, disruption of the murine methylated DNA binding protein 4 (Mbd4) gene, which encodes a DNA-glycosylase that removes thymine and uracil from mispairs with guanine 13., 14.•, was shown to result in an increased frequency of intestinal polyps in Mbd4^−/−Apc^Min/+ mice 15.••, 16..

All this evidence points to a link between DNA repair, transcriptional silencing and cancer, where the MMR system plays a pivotal role. In the following paragraphs we shall attempt to elucidate the nature of this link.

Section snippets

Mismatch repair defects

The study of mismatch-repair defects in cancer has received a great deal of attention since the discovery mentioned above of a connection between HNPCC and germline mutations in MMR genes. As this topic has been extensively reviewed in the recent literature 2., 3., 4., 6., 17., we shall focus here primarily on work with human cell lines and transgenic mouse models.

The principal players in mammalian MMR are the homologues of the bacterial MutS and MutL proteins, which function in the form of

Silencing of methylation damage reversal process

The MGMT protein plays an important role in DNA detoxification by removing small alkyl groups from the O⁶-position of guanines. This modification appears to be largely responsible for the cytotoxicity of methylating agents, as cells expressing high amounts of MGMT are resistant to killing by agents such as MNU, MNNG and temozolomide, whereas cells lacking this activity are highly sensitive to these drugs [40]. Patient- and organ-specific fluctuations in the levels of MGMT are thought to be

Base excision repair defects

Modification of DNA bases affects all organisms. The removal of these aberrant moieties is accomplished by several DNA glycosylases through cleavage of the glycosidic bonds. This gives rise to abasic (AP) sites. In mammalian cells, these non-informative lesions are excised from DNA by the concerted action of an AP-endonuclease, which cleaves the sugar-phosphate backbone on the 5′-side of the AP-site, and polymerase-β, which removes the baseless sugar-phosphate by β-elimination. The single

Conclusions

MMR defects were the first DNA repair malfunction to be linked with colon cancer. More recently, inactivation of MBD4 (MED1), MYH and MGMT, either through mutations or through transcriptional silencing, has also been implicated in this malignancy. It is curious to note that all three latter enzymes have also been shown to be linked with MMR, either through a direct interaction of the peptides concerned (MBD4 and MYH) or through a common substrate (MGMT). A detailed study of these interactions

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

•
of special interest
••
of outstanding interest

Acknowledgements

We would like to thank our colleagues for their contributions to this study and to apologize to all those whose work is not cited here because of restrictions of space.

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DNA repair defects in colon cancer

Abstract

Introduction

Section snippets

Mismatch repair defects

Silencing of methylation damage reversal process

Base excision repair defects

Conclusions

References and recommended reading

Acknowledgements

Curr. Opin. Genet Dev.

Mutat. Res.

Gastroenterology

Nat. Genet.

Hum. Mutat.

Nat. Med.

J. Biol. Chem.

J. Pathol.

EMBO J.

Proc. Natl. Acad. Sci. U.S.A.

Proc. Natl. Acad. Sci. U.S.A.

Cancer Res.

Proc. Natl. Acad. Sci. U.S.A.

Cancer Res.

Nat. Genet.

Mismatch repair in correction of replication errors and processing of DNA damage

J. Cell Physiol.

The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis

Cancer Res.

Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma

Proc. Natl. Acad. Sci. U.S.A.

Recent progress on the Ada response for inducible repair of DNA alkylation damage

Oncogene

CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future

Oncogene

Cloning and sequencing a human homolog (hMYH) of the Escherichia coli mutY gene whose function is required for the repair of oxidative DNA damage

J. Bacteriol.

Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors

Nat. Genet.

Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C→T:A mutations

Hum Mol. Genet

The thymine glycosylase MBD4 can bind to the product of deamination at methylated CpG sites

Nature

Investigation of the substrate spectrum of the human mismatch-specific DNA N-glycosylase MED1 (MBD4): fundamental role of the catalytic domain

J. Cell Physiol.

Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice

Science

Mbd4 inactivation increases C→T transition mutations and promotes gastrointestinal tumor formation

Proc. Natl. Acad. Sci. U.S.A.

Molecular mechanisms of DNA mismatch repair

Mutat. Res.

HNPCC-like cancer predisposition in mice through simultaneous loss of msh3 and msh6 mismatch-repair protein functions

Nat. Genet.

The distinct spectra of tumor-associated Apc mutations in mismatch repair-deficient Apc1638N mice define the roles of MSH3 and MSH6 in DNA repair and intestinal tumorigenesis

Cancer Res.

Identification of hMutLβ, a heterodimer of hMLH1 and hPMS1

J. Biol. Chem.

MLH3: a DNA mismatch repair gene associated with mammalian microsatellite instability

Nat. Genet.

The Saccharomyces cerevisiae MLH3 gene functions in MSH3-dependent suppression of frameshift mutations

Proc. Natl. Acad. Sci. U.S.A.

Meiotic arrest and aneuploidy in MLH3-deficient mice

Nat. Genet.

Different mutator phenotypes in Mlh1- versus Pms2-deficient mice

Proc. Natl. Acad. Sci. U.S.A.

Human exonuclease I is required for 5′ and 3′ mismatch repair

J. Biol. Chem.

Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms

Gastroenterology

A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor

Cancer Res.

Genetic and epigenetic alterations in colon cancer

Annu. Rev. Genomics. Hum. Genet.