Rmi1 is essential for DNA damage response and embryonic development in mice

Abstract

Suppression of Crossovers (CO) is critical for maintenance of genome integrity. CO may lead to loss of heterozygosity and CO between low‐copy repeats may account for many human disorders. Eukaryotes possess mechanisms that down regulate the number of CO. Indeed, BLM, the helicase mutated in Bloom syndrome, associates with topoisomerase IIIα and Rmi1 (RecQ‐mediated genome instability 1) to form a complex (the BLM dissolvasome) that efficiently control the number of CO by specifically resolving a key intermediate of recombination, the double Holliday junction (DHJ). To address the requirement of Rmi1 in mammals we generated knockout mice for this protein. Our results show that Rmi1 is required for normal embryonic development. Rmi1−/− knockout embryos die at 8.5 dpc, showing profound developmental defects reminiscent to those described for BLM−/− knockout mice. We obtained mouse embryonic fibroblasts from Rmi1−/− knockout and determined that these cells showed significantly reduced survival rates with respect to Rmi1+/− heterozygote and wild‐type controls. In this work, we will present a detailed characterization of developmental defects observed in Rmi1−/− knockout mice and study the DNA damage response of Rmi1 deficient cells. Our results will define how and when Rmi1 regulates the repair of DNA double‐stand breaks. This is important for understanding the mechanism by which somatic cells eliminate deleterious recombination products which are the root cause of genome instability and losses of heterozygosity.Financial support: OCAST