Program > Browse abstracts by speaker > Belancio Victoria

Long Interspersed Element 1 (L1) retrotransposons are endogenous mutagens that cause de novo inserts and DNA breaks. L1 overexpression can trigger apoptosis, senescence, large genomic deletions, and inflammatory response in cultured cells. Many of these events result from involvement of various cellular DNA repair pathways. Several DNA repair genes have been reported to suppress L1 retrotransposition in various experimental systems. However, how these genes and their defects affect L1 retrotransposition in normal mammalian environment remains poorly understood. We have developed a custom transgenic mouse model, harboring a single copy of a human L1 transgene to assess its mobilization in vivo. The L1Tg generates de novo inserts containing typical marks of authentic L1 integration. L1Tg-specific ddPCR analysis of DNA from large cohorts of wild type mice shows that the rate of L1Tg mobilization varies between genetic backgrounds. Breeding of these L1 transgenic mice with Xpc-deficient mice shows that a complete loss of Xpc increases de novo L1Tg retrotransposition. In contrast, Tp53-deficiency results in the decrease in de novo L1Tg mobilization in heterozygous and homozygous mice compared to the wild type mice. Changes in the L1 transgene retrotransposition in the germline or early embryo likely account for the observed differences in both Xpc- and Tp53-deficient mice. Our L1 transgenic mouse model and our findings open opportunities to investigate the health impact of L1 retrotransposition in vivo in the context of various genetic deficiencies and environmental exposures relevant to human diseases or their treatment. Our findings also reflect the complexity of L1 host interactions in mammalian systems that can be further exploited to understand mechanisms underlying heterogeneity in de novo L1 mobilization observed in the human population.