Involvement of tRNAs in replication of human mitochondrial DNA and modifying effects of telomerase.

ABSTRACT

Overexpression of telomerase has been shown to significantly increase the lifespan of mice. When mechanistically attributed to repair of critically short telomeres, the lifespan extending action of telomerase cannot be reconciled with the observation that telomerase-null mice do not exhibit shortening of lifespan for at least two generations. We hypothesized that telomerase may interfere with replication of mitochondrial DNA (mtDNA) in a way that reduces formation of deletions - the primary cause of age-dependent cell attrition in non-renewable cells such as myocytes and neurons. Here we show that several tRNA genes may function as alternative origins of replication (ORIs). We also show that telomerase interacts with canonical light strand ORI (ORIL) and tRNAs and modifies their activities. Our results suggest that replication of mitochondrial DNA (mtDNA) proceeds through a variety of mechanisms resulting in a mixture of classic strand-displacement mode, and coupled replication of heavy and light strands. Our results also suggest that effects of telomerase may arise from binding ORIL and thus limiting contribution of the deletion-prone strand displacement mode to mtDNA synthesis. These findings imply that it may be possible to uncouple detrimental and beneficial effects of telomerase, and thereby to improve telomerase-based strategies to extend lifespan.