TELOMERE ELONGATION BY HNRNP A1 AND A DERIVATIVE THAT INTERACTS WITH TELOMERIC REPEATS AND TELOMERASE

Telomeric DNA of mammalian chromosomes consists of several kilobase-pa irs of tandemly repeated sequences with a terminal 3' overhang in sing le-stranded form. Maintaining the integrity of these repeats is essent ial for cell survival; telomere attrition is associated with chromosom e instability and cell senescence, whereas stabilization of telomere l ength correlates with the immortalization of somatic cells(1), Telomer e elongation is carried out by telomerase, an RNA-dependent DNA polyme rase which adds single-stranded TAGGGT repeats to the 3' ends of chrom osomes'. While proteins that associate with single-stranded telomeric repeats can influence tract lengths in yeast(2,3), equivalent factors have not yet been identified in vertebrates. Here, it is shown that th e heterogeneous nuclear ribonucleoprotein Al participates in telomere biogenesis. A mouse cell line deficient in Al expression harbours telo meres that are shorter than those of a related cell line expressing no rmal levels of Al, Restoring Al expression in Al-deficient cells incre ases telomere length. Telomere elongation is also observed upon introd uction of exogenous UP1, the amino-terminal fragment of A1. While both Al and UP1 bind to vertebrate single-stranded telomeric repeats direc tly and with specificity in vitro, only UP1 can recover telomerase act ivity from a cell lysate. These findings establish A1/UP1 as the first single-stranded DNA binding protein involved in mammalian telomere bi ogenesis and suggest possible mechanisms by which UP1 may modulate tel omere length.