Characterizing small molecule inhibitors of the LINE1 endonuclease

Abstract

Our lab studies the mammalian mobile long interspersed element 1 (LINE1). LINE1 elements mobilize in the genome through a copy and paste itself into new genomic loci through the process of retrotransposition. The full‐length LINE1 element is comprised of two open reading frames, ORF‐1 and ORF‐2. The latter protein, ORF‐2, encodes an endonuclease, which is responsible for nicking DNA near the adenine‐thymine rich base sequence. Proper functioning of LINE1 endonuclease facilitates the mobilization of the element and requires the formation of DNA damage in the form of double‐strand breaks (DSBs), which could, in turn, lead to diseases such as cancer. Approximately eighteen percent of the human genome is comprised of the LINE1 sequence and the expression of LINE1 proteins and mobilization of the LINE1 element has been implicated in several cancers, such as breast and prostate cancers. While events of LINE1 insertion may be mutagenic, the effect of the LINE1 endonuclease on genetic instability is unclear. If the DNA DSBs associated with LINE1 endonuclease are not repaired faithfully, then mutations may result that lead to disease onset or progression. In our laboratory we have identified small molecule inhibitors of the LINE1 endonuclease. Here we present our work investigating the impact of the small molecule inhibitors on the formation of LINE1 endonuclease associated DNA DSBs.Support or Funding InformationThe work presented is supported in part by monies from P20GM103424, TL4GM118968 and 5RL5GM118966‐03 as well as the Louisiana Cancer Research Consortium. We also thank the Molecular and Cellular Biology core at Xavier University of Louisiana.