Functional analyses of human DNA repair proteins important for aging and genomic stability using yeast genetics

Aggarwal, Monika; Brosh, Robert M.

doi:10.1016/j.dnarep.2012.01.013

Cited by 12 publications

(5 citation statements)

References 165 publications

(174 reference statements)

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“…In recent years, several yeast-based assays have been developed to study the biological function of human genes involved in breast, ovarian, and colon cancers (Aggarwal & Brosh, 2012;Millot et al, 2012;Rasmussen et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

The expanding role of yeast in cancer research and diagnosis: insights into the function of the oncosuppressors p53 and BRCA1/2

et al. 2013

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When the glucose supply is high, despite the presence of oxygen, Saccharomyces cerevisiae uses fermentation as its main metabolic pathway and switches to oxidative metabolism only when this carbon source is limited. There are similarities between glucose-induced repression of oxidative metabolism of yeast and metabolic reprogramming of tumor cells. The glucose-induced repression of oxidative metabolism is regulated by oncogene homologues in yeast, such as RAS and Sch9p, the yeast homologue of Akt. Yeast also undergoes an apoptosis-like programmed cell death process sharing several features with mammalian apoptosis, including oxidative stress and a major role played by mitochondria. Evasion of apoptosis and sustained proliferative signaling are hallmarks of cancer. This, together with the possibility of heterologous expression of human genes in yeast, has allowed new insights to be obtained into the function of mammalian oncogenes/oncosuppressors. Here, we elaborate on the similarities between tumor and yeast cells underpinning the use of this model organism in cancer research. We also review the achievements obtained through heterologous expression in yeast of p53, BRCA1, and BRCA2, which are among the best-known cancer-susceptibility genes, with the aim of understanding their role in tumorigenesis. Yeast-cell-based functional assays for cancer genetic testing will also be dealt with.

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Section: Discussionmentioning

confidence: 99%

The expanding role of yeast in cancer research and diagnosis: insights into the function of the oncosuppressors p53 and BRCA1/2

et al. 2013

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“…It is noteworthy that among the large number of polymorphisms tested in this study, only a few functional SNPs could be conclusively identified with supporting evidence. These genes, which encode proteins that are involved in steroid action, cell cycle control and DNA repair pathways, are highly conserved [52,53], and therefore, the likelihood of finding common functional variants with a large effect on these genes is almost null due to the major role they play in the maintenance of the genomic integrity. Nonetheless, while small variations in the expression level of these genes might functionally impact their expression, transient transfection assays might not be the appropriate method to detect such small effects.…”

Section: Discussionmentioning

confidence: 99%

Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control

Hamdi

Leclerc

Dumont

et al. 2019

Genes

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Genetic variants affecting the regulation of gene expression are among the main causes of human diversity. The potential importance of regulatory polymorphisms is underscored by results from Genome Wide Association Studies, which have already implicated such polymorphisms in the susceptibility to complex diseases such as breast cancer. In this study, we re-sequenced the promoter regions of 24 genes involved in pathways related to breast cancer including sex steroid action, DNA repair, and cell cycle control in 60 unrelated Caucasian individuals. We constructed haplotypes and assessed the functional impact of promoter variants using gene reporter assays and electrophoretic mobility shift assays. We identified putative functional variants within the promoter regions of estrogen receptor 1 (ESR1), ESR2, forkhead box A1 (FOXA1), ubiquitin interaction motif containing 1 (UIMC1) and cell division cycle 7 (CDC7). The functional polymorphism on CDC7, rs13447455, influences CDC7 transcriptional activity in an allele-specific manner and alters DNA–protein complex formation in breast cancer cell lines. Moreover, results from the Breast Cancer Association Consortium show a marginal association between rs13447455 and breast cancer risk (p=9.3x10-5), thus warranting further investigation. Furthermore, our study has helped provide methodological solutions to some technical difficulties that were encountered with gene reporter assays, particularly regarding inter-clone variability and statistical consistency.

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“…Furthermore, construction of gene deletion strains, tagging proteins and site-specific mutagenesis are easier and faster than in human cells. Therefore, construction of "humanized" yeast, meaning a yeast strain expressing human genes or carrying mutation in an endogenous gene homologous to the human one, can be helpful in evaluating the functional consequences of human genetic variants found in several diseases [45][46][47][48]. When the yeast counterpart exists, functional assays can be developed by directly mutating the genomic copy of the yeast homologous gene ( Figure 1A).…”

Section: Yeast-based Functional Assays On Dna Repair Human Genesmentioning

confidence: 99%

Yeast-based assays for the functional characterization of cancer-associated variants of human DNA repair genes

et al. 2020

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Technological advances are continuously revealing new genetic variants that are often difficult to interpret. As one of the most genetically tractable model organisms, yeast can have a central role in determining the consequences of human genetic variation. DNA repair gene mutations are associated with many types of cancers, therefore the evaluation of the functional impact of these mutations is crucial for risk assessment and for determining therapeutic strategies. Owing to the evolutionary conservation of DNA repair pathways between human cells and the yeast Saccharomyces cerevisiae, several functional assays have been developed. Here, we describe assays for variants of human genes belonging to the major DNA repair pathways divided in functional assays for human genes with yeast orthologues and human genes lacking a yeast orthologue. Human genes with orthologues can be studied by introducing the correspondent human mutations directly in the yeast gene or expressing the human gene carrying the mutations; while the only possible approach for human genes without a yeast orthologue is the heterologous expression. The common principle of these approaches is that the mutated gene determines a phenotypic alteration that can vary according to the gene studied and the domain of the protein. Here, we show how the versatility of yeast can help in classifying cancer-associated variants.

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Functional analyses of human DNA repair proteins important for aging and genomic stability using yeast genetics

Cited by 12 publications

References 165 publications

The expanding role of yeast in cancer research and diagnosis: insights into the function of the oncosuppressors p53 and BRCA1/2

The expanding role of yeast in cancer research and diagnosis: insights into the function of the oncosuppressors p53 and BRCA1/2

Functional Analysis of Promoter Variants in Genes Involved in Sex Steroid Action, DNA Repair and Cell Cycle Control

Yeast-based assays for the functional characterization of cancer-associated variants of human DNA repair genes

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