The role of DBF4 in homologous recombination and genomic stability

• Grant number: 15/20349-3
• Support Opportunities: Scholarships abroad - Research
• Start date: March 09, 2016
• End date: March 08, 2017
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Maria Cristina da Silva Pranchevicius
• Grantee: Maria Cristina da Silva Pranchevicius
• Host Investigator: Roberto J. Pezza
• Host Institution: Centro de Ciências Biológicas e da Saúde (CCBS). Universidade Federal de São Carlos (UFSCAR). São Carlos , SP, Brazil
• Institution abroad: Oklahoma Medical Research Foundation (OMRF), United States

Abstract

At initial steps of meiosis, a number of DNA double-strand breaks (DSBs) are introduced, which initiate homologous recombination (HR). HR promotes exchange of genetic information between homologous chromosomes and promotes accurate chromosome segregation. This is required for the formation of gametes with the correct number of chromosomes and avoidance of human aneuploidy. Given the possible deleterious consequences of incomplete or incorrect meiotic DNA repair, cells have evolved a number of mechanisms to ensure a tight control of DSB formation and repair. The Dbf4-dependent Cdc7 kinase complex (DDK) provides a link between pre-meiotic S-phase and recombination. Independently from its established role in initiating DNA replication, DDK promotes double-strand break formation, the first step of recombination.Interestingly, DDK has an increased expression in e cancer cell lines derived from diverse tissues. Therefore, high Cdc7-Dbf4 level may be linked to malignant cell transformation and tumor development, which in turn suggests a biological, prognostic, and therapeutic applications of Cdc7-Dbf4 kinase complex in cancer therapy. Despite its well-characterized function for DNA replication in the mitotic cell cycle, little is known about the role of DDK during meiosis, especially Dbf4. Thus, the focus of this study is to provide a better understanding of the in vivo roles of Dbf4 in DNA repair in development and in adult tissues using the mouse model. This work will report for the first time the phenotypic characterization of Dbf4-/- mice in both mitotic and meiotic cells. The data obtained and the mouse model will be valuable resources for both national and international research communities. (AU)