Long interspersed element ‐1 (LINE‐1) is a mobile element, or jumping gene, which employs a “copy and paste” method called retrotransposition to insert itself into the human genome. This retrotransposition mechanism utilizes an enzyme called the L1 endonuclease to initiate the double strand breaks necessary for LINE‐1 insertion. Studies have found that a significant portion of the human genome is composed of mobile elements, which have likely played a crucial evolutionary role in the current genetic variability observed in humans. However, in some instances the mutations that have arisen from increased LINE‐1 retrotransposition, have been linked to genetic diseases such as colon cancer, breast cancer, and have been linked to genome instability due to increased double strand breaks. Previous research suggests that heavy metals such as Ni2+, Co2+, and Cd2+, which occur in our industrialized environment as pollutants, potentially affect levels of LINE‐1 retrotransposition. These toxic metals have been observed to compete with Mg2+ as cofactors for proteins, and have been observed to inhibit essential reactions in DNA repair. Competition with Mg as a cofactor suggests these heavy metals likely have an effect on levels of LINE‐1 endonuclease activity in vitro since it also utilizes Mg2+ as a cofactor for enzymatic activity. We focused on the effects that the heavy metals cobalt and cadmium have on the LINE‐1 endonuclease activity to determine whether or not these metals also influence levels of double strand breaks in vitro. Preliminary results indicate that the metal cobalt does not prevent LINE‐1 endonuclease activity at doses up to 100uM.Support or Funding InformationThis work was funded by an Institutional Development Award (IDeA) from the NIGMS under grant number P20GM103424 and from the Louisiana Cancer Research Consortium, the NIH‐RCMI grant #8G12MD007595‐05.

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.