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Your search keyword '"Lodovichi, Samuele"' showing total 17 results
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17 results on '"Lodovichi, Samuele"'

12. Effect of BRCA1 missense variants on gene reversion in DNA double-strand break repair mutants and cell cycle-arrested cells of Saccharomyces cerevisiae.

Author

Lodovichi, Samuele, Bellè, Francesca, Cervelli, Tiziana, Lorenzoni, Alessandra, Maresca, Luisa, Cozzani, Cristina, Caligo, Maria Adelaide, and Galli, Alvaro

Subjects
*DOUBLE-strand DNA breaks, *SACCHAROMYCES cerevisiae, *DNA analysis, *SINGLE-stranded DNA, *CELL cycle, *GENES
Abstract

Evaluation of the functional impact of germline BRCA1 variants that are likely to be associated to breast and ovarian cancer could help to investigate the mechanism of BRCA1 tumorigenesis. Expression of pathogenic BRCA1 missense variants increased homologous recombination (HR) and gene reversion (GR) in yeast. We thought to exploit yeast genetics to shed light on BRCA1-induced genome instability and tumorigenesis. We determined the effect on GR of several neutral and pathogenic BRCA1 variants in the yeast strain RSY6wt and its isogenic DSB repair mutants, such as mre11∆ , rad50∆ and rad51∆. In the RSY6wt, four out of five pathogenic and two out of six neutral variants significantly increased GR; rad51∆ strain, the pathogenic variants C61G and A1708E induced a weak but significant increase in GR. On the other hand, in rad50∆ mutant expressing the pathogenic variants localised at the BRCT domain, a further GR increase was seen. The neutral variant N132K and the VUS A1789T induced a weak GR increase in mre11∆ mutant. Thus, BRCA1 missense variants require specific genetic functions and presumably induced GR by different mechanisms. As DNA repair is regulated by cell cycle, we determined the effect on GR of BRCA1 variants in cell cycle-arrested RSYwt cells. GR is highly BRCA1-inducible in S-phase-arrested cells as compared to G1 or G2. Sequence analysis of genomic DNA from ILV1 revertant clones showed that BRCA1-induced ilv1-92 reversion by base substitution when GR is at least 6-fold over the control. Our study demonstrated that BRCA1 may interfere with yeast DNA repair functions that are active in S-phase causing high level of GR. In addition, we confirmed here that yeast could be a reliable model to investigate the mechanism and genetic requirements of BRCA1-induced genome instability. Finally, developing yeast-based assays to characterise BRCA1 missense variants could be useful to design more precise therapies. [ABSTRACT FROM AUTHOR]

Published
2020
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13. Functional Interaction Between BRCA1 and DNA Repair in Yeast May Uncover a Role of RAD50, RAD51, MRE11A, and MSH6 Somatic Variants in Cancer Development

Author

Maresca, Luisa, primary, Lodovichi, Samuele, additional, Lorenzoni, Alessandra, additional, Cervelli, Tiziana, additional, Monaco, Rossella, additional, Spugnesi, Laura, additional, Tancredi, Mariella, additional, Falaschi, Elisabetta, additional, Zavaglia, Katia, additional, Landucci, Elisabetta, additional, Roncella, Manuela, additional, Congregati, Caterina, additional, Gadducci, Angiolo, additional, Naccarato, Antonio Giuseppe, additional, Caligo, Maria Adelaide, additional, and Galli, Alvaro, additional

Published
2018
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17. Expression of cancer related BRCA1 missense variants decreases MMS-induced recombination in Saccharomyces cerevisiaewithout altering its nuclear localization

Author

Lodovichi, Samuele, Vitello, Martina, Cervelli, Tiziana, and Galli, Alvaro

Abstract

ABSTRACTBRCA1tumor suppressor gene is found mutated in familial breast and ovarian cancer. Most cancer related mutations were found located at the RING (Really Interesting New Gene) and at the BRCT (BRca1 C-Terminal) domain. However, 20 y after its identification, the biological role of BRCA1 and which domains are more relevant for tumor suppression are still being elucidated. We previously reported that expression of BRCA1 cancer related variants in the RING and BRCT domain increases spontaneous homologous recombination in yeast indicating that BRCA1 may interact with yeast DNA repair/recombination. To finally demonstrate whether BRCA1 interacts with yeast DNA repair, we exposed yeast cells expressing BRCA1wt, the cancer-related variants C-61G and M1775R to different doses of the alkylating agent methyl methane-sulfonate (MMS) and then evaluated the effect on survival and homologous recombination. Cells expressing BRCA1 cancer variants were more sensitive to MMS and less inducible to recombination as compared to cell expressing BRCA1wt. Moreover, BRCA1-C61G and -M1775R did not change their nuclear localization form as compared to the BRCA1wt or the neutral variant R1751Q indicating a difference in the DNA damage processing. We propose a model where BRCA1 cancer variants interact with the DNA double strand break repair pathways producing DNA recombination intermediates, that maybe less repairable and decrease MMS-induced recombination and survival. Again, this study strengthens the use of yeast as model system to characterize the mechanisms leading to cancer in humans carrying the BRCA1 missense variant.

Published
2016
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