Nucleoside analogue reverse transcriptase inhibitors differentially inhibit human LINE-1 retrotransposition.
BACKGROUND
Intact LINE-1 elements are the only retrotransposons encoded by the human genome known to be capable of autonomous replication. Numerous cases of genetic disease have been traced to gene disruptions caused by LINE-1 retrotransposition events in germ-line cells. In addition, genomic instability resulting from LINE-1 retrotransposition in somatic cells has been proposed as a contributing factor to oncogenesis and to cancer progression. LINE-1 element activity may also play a role in normal physiology.


RESULTS
Using an in vitro LINE-1 retrotransposition reporter assay, we evaluated the abilities of several antiretroviral compounds to inhibit LINE-1 retrotransposition. The nucleoside analogue reverse transcriptase inhibitors (nRTIs): stavudine, zidovudine, tenofovir disoproxil fumarate, and lamivudine all inhibited LINE-1 retrotransposition with varying degrees of potencies, while the non-nucleoside HIV-1 reverse transcriptase inhibitor nevirapine showed no effect.


CONCLUSIONS
Our data demonstrates the ability for nRTIs to suppress LINE-1 retrotransposition. This is immediately applicable to studies aimed at examining potential roles for LINE-1 retrotransposition in physiological processes. In addition, our data raises novel safety considerations for nRTIs based on their potential to disrupt physiological processes involving LINE-1 retrotransposition.
Jones
R Brad
RB
Department of Immunology, University of Toronto, Medical Sciences Building, Toronto, Ontario, Canada. brad.jones@utoronto.ca
Garrison
Keith E
KE
Wong
Jessica C
JC
Duan
Erick H
EH
Nixon
Douglas F
DF
Ostrowski
Mario A
MA
D004341:Drug Evaluation; D064420:Drug-Related Side Effects and Adverse Reactions; D015894:Genome, Human; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000187:drug effects* / Q000235:genetics; D009705:Nucleosides / Q000009:adverse effects / Q000737:chemistry; D018626:Retroelements / Q000187:drug effects*; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000737:chemistry
D009705:Nucleosides; D018626:Retroelements; D018894:Reverse Transcriptase Inhibitors