The beginning of the end: Links between ancient retroelements and modern telomerases
- Wadsworth Center, New York State Department of Health, 150 New Scotland Avenue, Albany, NY 12208
Molecular and evolutionary biologists have long debated the origin of telomerases, the enzymes that maintain chromosome ends (1, 2). These ends, called telomeres, are nucleoprotein structures that consist of repetitive DNA sequences bound by specific proteins. Telomeres serve two basic functions: they distinguish chromosome termini from double-strand breaks, and they counteract the erosion of linear chromosomes from their ends. Telomerase, a ribonucleoprotein (RNP) composed of a reverse transcriptase (RT) and an RNA encoded by a different gene (3, 4), synthesizes the telomeric DNA repeats by using the 3′-OH at the end of the chromosome as a primer and telomerase RNA as a template (Fig. 1 A). It is assumed that linear eukaryotic chromosomes have coevolved with telomerase. But the question remains, how did their association arise?
Telomerases and retrotransposons. (A) RTs at telomere and within chromosome (black lines with gray circle). TERT acts on 3′-OH at telomere, whereas the RT of endonuclease-proficient TP-retrotransposons acts on the 3′-OH at a double-strand break. The wavy line indicates RNA. (B) Structure. The canonical nuclease-proficient PLE consists of a single ORF comprising RT and a GIY-YIG endonuclease. Terminal PLEs lack the endonuclease domain, but contain a 5′ ORF with similarity to ORF1 of L1 elements, depicted below. The RT of L1 contains an AP-endonuclease domain (AP, apurinic/apyrimidinic). (C) Mechanism. PLE retrotransposition occurs when repeat sequences near the 3′ end of PLE RNA hybridize to a telomeric DNA repeat (TGAGGG) at the single-stranded 3′ end of the chromosome. With the 3′ OH as a primer, RT synthesizes cDNA (blue) from the PLE RNA template. The second (bottom) strand of DNA is presumably synthesized by host-mediated DNA replication. RT dissociates from the PLE RNA prematurely, creating a 5′ truncated cDNA, which is capped with telomeric DNA repeats (purple) by telomerase. Retrotransposition of the endonuclease-deficient …
*To whom correspondence should be addressed. E-mail: belfort{at}wadsworth.org
