The Human Pif1 Encodes A RecD-like Helicase That Regulates Telomere Elongation Through Inhibition Of Telomerase Activity

Telomeres are nucleoprotein structures that are positioned at eukaryotic linearchromosomal ends. The primary role of telomeres is to insulate the chromosomal endsfrom both fusion with other ends and from nucleolytic digestion. The stablemaintenance of telomeres contributes to genome stability, and correlates with cancerand aging. The telomerase is a specialized reverse transcriptase that extends the 3' endof the G-rich strand of telomeres.The Saccharomyces Pif1 helicase inhibits telomere lengthening through thetelomerase pathway. Pif1-like genes are found in diverse organisms. Because thefundamental mechanism of telomere replication is highly conserved from yeast tomammals, we want to know whether hPif1 exists, and what the role of hPif1 plays inhuman. Here, we identified a human helicase, hPif1, that inhibits telomerase activity.The primary sequence and biochemical analysis suggest that hPif1 is a potentialhomologue of Escherichia coli RecD, an ATP-dependent 5' to 3' DNA helicase.Ectopic expression of wild-type, but not the ATPase/helicase deficient hPif1, causestelomere shortening in HT1080 cells. hPif1 inhibits human telomerase activityprobably due to reducing the repeat addition processivity of telomerase in vitro. hPif1could unwind DNA/RNA duplex and preferentially binds telomeric DNA in vitro andin vivo. We propose that the inhibitory mechanism of hPif1 on telomerase involvesunwinding of the DNA/RNA duplex formed by telomerase RNA and telomeric DNA.RecD homologues in eukaryotes may have evolved gaining additional functions.