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Analysis of mutation rate in offspring born to mice with oocyte-specific deficiency of Rad51

Grant number: 22/09281-1
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2022
Effective date (End): July 31, 2023
Field of knowledge:Biological Sciences - Genetics - Mutagenesis
Principal Investigator:Nadja Cristhina de Souza Pinto
Grantee:Renan Omete Ferreira
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:17/04372-0 - Mitochondrial DNA: mechanisms for genome integrity maintenance and impact on disease, AP.TEM

Abstract

The expression of key genes required for DNA repair by homology such as Brca1, Mre11, Rad51 and Atm decreases in oocytes during aging, resulting in a progressive increase in double-strand breaks (DSB) in DNA and infertility. In keeping with these findings, our data support that the conditional deletion of Rad51 in mouse oocytes results in subfertility characterized by a significant decrease in the number of pups born per female and per litter, in addition to a decrease in the number of litter per female. This subfertility, however, cannot be attributed to a defect in oogenesis once Rad51-deficient oocytes are normal regarding their morphology, size, mitochondrial activity, ATP content and gene expression. Female mice with oocyte-specific deletion of Rad51 also ovulate an expected number of viable oocytes. Nonetheless, analysis of H2AX phosphorylation at serine 139 indicates that Rad51 deficiency results in an increase in DSBs in oocytes and embryos, which seems to impair cellular viability after fertilization. In summary, our findings provide evidence that Rad51 is needed in the oocyte to assure its genetic stability of offspring. Therefore, our aim is to determine the mutation rate in mice born to females with oocyte-specific deficiency of Rad51. We expect from this analysis to demonstrate that Rad51 is needed in the oocyte to mitigate mutation transmission to offspring.

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