DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

Heinen, Christopher D.; Schmütte, Christoph; Fishel, Richard

doi:10.4161/cbt.1.5.160

Cited by 108 publications

(71 citation statements)

References 91 publications

(125 reference statements)

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“…Hence, the present work has relevance to a number of topics in cancer research. It is intriguing that the only MMR gene found to be epigenetically down-regulated in human mutator tumors is the mutL ortholog hMLH1 (41 Determination of Deletion Frequencies. Bacterial cultures were inoculated with Ͻ100 cells to ensure that no preexisting lacZ ϩ cells were present in the starting inoculum.…”

Section: Discussionmentioning

confidence: 99%

The frequency and structure of recombinant products is determined by the cellular level of MutL

Elez

Radman

Matić

2007

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

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The presence of repeated DNA sequences is a genomic liability, because interrepeat recombination can result in chromosomal rearrangements. The mismatch repair system prevents recombination between nonidentical repeats, but the mechanism of antirecombination has not been established. Although the MutS protein binds to base pair mismatches in heteroduplex DNA, the role of the MutL protein in preventing recombination is unknown. In a screen designed to identify new cellular functions that suppress deletion formation involving nonidentical DNA repeats, we isolated a mutL mutant having a separation-of-function phenotype. The mutant showed an increased frequency of deletions but not of mutations. The split phenotype is due to a decreased MutL level, indicating that recombination, but not replication editing, is highly sensitive to MutL level. By altering the MutL level, we found that the frequency of deletion-generating recombination is inversely related to the amount of cellular MutL. DNA sequence analysis of the recombined repeats shows that the tolerance of base pair mismatches in heteroduplex DNA is also inversely correlated with MutL level. Unlike recombination, correction of misincorporation errors by mismatch repair is insensitive to fluctuations in MutL level. Overproduction of MutS does not affect either of these phenotypes, suggesting that, unlike MutL, MutS is not limiting for mismatch repair activities. These results indicate that MutL (i) determines effective DNA homology in recombination processes and (ii) fine tunes the process of deletion formation involving repeated, diverged DNA sequences.deletions ͉ DNA repeats ͉ mismatch repair ͉ recombination ͉ replication P rokaryotic genomes are riddled with DNA sequence repeats, which are found in intergenic regions, genes, and transposable elements (1). Repeats are even more abundant in eukaryotic genomes (2), and at least 34% of the human genome consists of such sequences (3). The presence of dispersed repeated DNA sequences is a genetic liability because interrepeat recombination can cause deletions, duplications, inversions or translocations, depending on the configuration and orientation of the repeat units. In humans, recombination between repeats is at the origin of disease-causing deletions, such as ␣-thalassemias, Duchenne muscular dystrophy, and familial hypercholesterolemia (4-7).Recombination between repeats is constantly initiated by DNA damage and/or DNA replication blockage that results from exogenous and endogenous genomic insults. Therefore, natural selection for genome stability has resulted in the emergence of mechanisms that prevent interrepeat recombination. Newly arising repeats are identical at the DNA sequence level, but established repeats have usually diverged (8). The degree and distribution of sequence divergence are structural parameters that influence recombination between repeats because they affect the activity of recombination enzymes and determine whether the antirecombinogenic activity of mismatch repair (MMR) proteins is trig...

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Section: Discussionmentioning

confidence: 99%

The frequency and structure of recombinant products is determined by the cellular level of MutL

Elez

Radman

Matić

2007

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

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“…About 90% of HNPCC cases display MSI. MSI has been uniquely linked with mismatch repair defects, so MSI can be used as a marker for mutator phenotype to diagnose patients at high risk for HNPCC [40] .…”

Section: Role Of Dna Mismatch Repair Proteins In Hnpccmentioning

confidence: 99%

“…HNPCC is a caused by inherited germ line mutations in one of the mismatch repair genes especially MLH1 and MSH2 [31,40] . About 90% of HNPCC cases display MSI.…”

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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“…DNA repair mechanisms play a major role in protecting against carcinogenesis and genetic defect in DNA repair can cause human cancer (Heinen et al, 2002). Through repairing DNA damage and maintaining genetic stability, PARP-1 has played an important role in prevention of carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…DNA repair pathways exist in all cells for maintaining genome integrity (Hoeijmakers, 2001), and mutations within these pathways can result in cancer (Heinen et al, 2002). Interindividual variations in DNA damage and repair have been associated with an increased risk of breast cancer (Johnson et al, 2000;Tyrer et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

The C Allele of a Synonymous SNP (rs1805414, Ala284Ala) in PARP1 is a Risk Factor for Susceptibility to Breast Cancer in Saudi Patients

Alanazi

Pathan²,

Shaik³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background: Genetic aberrations of DNA repair enzymes are known to be common events associated with different cancer entities. The aim of the present study was to analyze genetic associations of rs1805404 (Asp81Asp) and rs1805414 (Ala284Ala) in the PARP1 gene with the risk of breast cancer in Saudi Arabia. Materials and Methods: These two SNP's were analyzed in a primary study group of breast cancer patients and healthy control subjects. Genotypes were determined by TaqMan SNP testing and analyzed using Chi-square or t test and logistic regression analysis with SPSS16.0 software. Results and Conclusions: Results showed that rs1805414 was associated with a significantly increased susceptibility to breast cancer, significant risk being observed for the TC, CC and TC+CC genotypes. In conclusion PARP1 rs1805414 SNP polymorphisms may be involved in the etiology of breast cancer in the Saudi population. In contrast, PARP1 rs1805404 did not show any significant association in overall in breast cancer samples when compared to healthy controls. Confirmation of our findings in larger populations of different ethnicities may provide evidence for a role of the PARP1 gene in breast carcinoma developnment.

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DNA Repair and Tumorigenesis: Lessons from Hereditary Cancer Syndromes

Cited by 108 publications

References 91 publications

The frequency and structure of recombinant products is determined by the cellular level of MutL

The frequency and structure of recombinant products is determined by the cellular level of MutL

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

The C Allele of a Synonymous SNP (rs1805414, Ala284Ala) in PARP1 is a Risk Factor for Susceptibility to Breast Cancer in Saudi Patients

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