The generation of long telomere overhangs in human cells: a model and its implication

MOTIVATION: Linear chromosomes carry on both ends repetitive DNA sequences called telomere. In the conventional model of semi-conservative DNA replication, the 3'-end of a linear DNA strand cannot be fully replicated, resulting in a single-stranded 3' overhang at one end of the double-stranded DNA product. In this model, the length of the overhang is expected to be about the size of an RNA primer (about nine nucleotides for human cells). However, it has been found that the telomere overhangs in human cells can be as long as several hundred nucleotides. At present, the opinion regarding how such long overhangs are produced is controversial. RESULTS: In order to gain insight into the mechanism by which long telomere overhangs are produced, we derived a mathematical model that can perfectly describe the length distribution of telomere overhangs in several human cell strains. The model suggests that the production of telomere overhangs can be explained by three contributions corresponding to three regions on the G-rich telomere template strand, namely, the region occupied by the last primer, that missed out by this primer at its 5'-side and the 3'-terminus of the template strand that is inaccessible to primase. The model can also be used to simulate incomplete telomere replication.