DNA mismatch repair defects: role in colorectal carcinogenesis

Jacob, S.; Praz, Françoise

doi:10.1016/s0300-9084(01)01362-1

Cited by 117 publications

(76 citation statements)

References 244 publications

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“…Interestingly, the human homolog of Dpb2p (POLE2) has 44% overall amino acid homology to the yeast Dpb2 protein (Li et al 1997). It was previously shown that MMR defects destabilizing DNA occur in several tumor cell lines, particularly those from colon cancers (Kolodner 1996;Kolodner and Marsischky 1999;Jacob and Praz 2002). Several cancer susceptibility syndromes that are due to inherited mutations in genes whose products function in response to DNA damage and DNA recombination/repair have been described.…”

Section: Discussionmentioning

confidence: 99%

Dpb2p, a Noncatalytic Subunit of DNA Polymerase ε, Contributes to the Fidelity of DNA Replication in Saccharomyces cerevisiae

et al. 2008

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Most replicases are multi-subunit complexes. DNA polymerase epsilon from Saccharomyces cerevisiae is composed of four subunits: Pol2p, Dpb2p, Dpb3p, and Dpb4p. Pol2p and Dpb2p are essential. To investigate a possible role for the Dpb2p subunit in maintaining the fidelity of DNA replication, we isolated temperaturesensitive mutants in the DPB2 gene. Several of the newly isolated dpb2 alleles are strong mutators, exhibiting mutation rates equivalent to pol2 mutants defective in the 39 / 59 proofreading exonuclease (pol2-4) or to mutants defective in mismatch repair (msh6). The dpb2 pol2-4 and dpb2 msh6 double mutants show a synergistic increase in mutation rate, indicating that the mutations arising in the dpb2 mutants are due to DNA replication errors normally corrected by mismatch repair. The dpb2 mutations decrease the affinity of Dpb2p for the Pol2p subunit as measured by two-hybrid analysis, providing a possible mechanistic explanation for the loss of high-fidelity synthesis. Our results show that DNA polymerase subunits other than those housing the DNA polymerase and 39 / 59 exonuclease are essential in controlling the level of spontaneous mutagenesis and genetic stability in yeast cells.

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Section: Discussionmentioning

confidence: 99%

Dpb2p, a Noncatalytic Subunit of DNA Polymerase ε, Contributes to the Fidelity of DNA Replication in Saccharomyces cerevisiae

et al. 2008

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“…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] . DNA mismatch repair was first discovered in bacteria where it was identified.…”

Section: Role Of Dna Mismatch Repair Proteins In Hnpccmentioning

confidence: 99%

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

Hassen

Ali²,

Chowdhury³

2012

WJGP

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Colorectal cancer is the second most leading cause of cancer related deaths in the western countries. One of the forms of colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC), also known as "Lynch syndrome". It is the most common hereditary form of cancer accounting for 5%-10% of all colon cancers. HNPCC is a dominant autosomal genetic disorder caused by germ line mutations in mismatch repair genes. Human mismatch repair genes play a crucial role in genetic stability of DNA, the inactivation of which results in an increased rate of mutation and often a loss of mismatch repair function. Recent studies have shown that certain mismatch repair genes are involved in the regulation of key cellular processes including apoptosis. Thus, differential expression of mismatch repair genes particularly the contributions of MLH1 and MSH2 play important roles in therapeutic resistance to certain cytotoxic drugs such as cisplatin that is used normally as chemoprevention. An understanding of the role of mismatch repair genes in molecular signaling mechanism of apoptosis and its involvement in HNPCC needs attention for further work into this important area of cancer research, and this review article is intended to accomplish that goal of linkage of apoptosis with HNPCC. The current review was not intended to provide a comprehensive enumeration of the entire body of literature in the area of HNPCC or mismatch repair system or apoptosis; it is rather intended to focus primarily on the current state of knowledge of the role of mismatch repair proteins in molecular signaling mechanism of apoptosis as it relates to understanding of HNPCC.

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“…About 5-10% of breast cancers are inherited, one-third of which are caused by dominant BRCA-gene mutations (Xu et al, 2011). Research has previously focused on the protein-coding genes such as oncogenes, tumor suppressor genes, DNA repair genes, and anti-metastatic genes in cancer genetics (Jacob & Praz , 2002;Rabien et al, 2011).…”

Section: Introductionmentioning

confidence: 99%