Mammalian retrotransposons in development and disease
Mammalian L1 retrotransposons are among the most abundant and still active retroelements in the human genome. Besides acting as endogenous mutagen by inserting into the genes after retrotransposition, L1 retrotransposon has potential to damage the genome through creation of DNA breaks generated during retrotransposition. Thus, L1 retrotransposition needs to be tightly regulated. There is an increasing evidence of elevated activity of L1 in cancer and in the mouse models of sterility, but a causative relationship hasn't been established. L1 is also very active in the brain, but the consequences of this activity are not clear.
One of my projects focuses on finding small molecule inhibitors for endonuclease activity of L1. We have done an in silico screen for small molecules inhibitors of human L1 endonuclease based on crystal structure of L1 endonuclease and molecular docking of 600 000 available small molecule structures. We are currently testing top candidates biochemically and in cell based assays for inhibition of L1 endonuclease activity. The ultimate goal of this project is to test their inhibitory activity in mouse models of sterility and cancer. These compounds could potentially be effective for treatment of various diseases where L1 activity has been implicated.
My second project focuses on examining whether there is a connection between human sterility and L1 retrotransposons. There are numerous cases of human male sterility where the cause is unknown. Given the association of transposon dysregulation and sterility in all model organisms tested, we hypothesize that increased L1 activity may be associated with some cases of sterility in humans. Depending on the outcome of this study, we are planning on extending the analysis on these samples to look for possible genetic causes for the loss of L1 regulation.