Spontan Replikasyon Çatalı Çökmesi, Sadece Kromozom Uçları Değil, Telomer Uzunluğu Homeostazisini Belirliyor

Özet (abstract)

Abstract In most eukaryotes, the enzyme telomerase maintains the termini of linear chromosomes through the addition of repetitive telomeric sequences. It is widely assumed that the primary site of action for telomerase is the single-stranded G-rich overhang at the ends of linear chromosomes. We show here that a second substrate, created by spontaneous replication fork collapse during duplex telomeric DNA replication in wild type budding yeast, is elongated by telomerase at a much higher frequency (∼50%) than fully replicated chromosome termini. Furthermore, as much as ∼200 nucleotides can be added in a single cell division to these newly collapsed forks, indicating that spontaneous replication fork collapse and the subsequent response by telomerase is a major determinant of telomere length homeostasis. This challenges a long-standing model for telomere length regulation which posits a length-sensing mechanism that assesses individual telomeres to determine whether chromosome ends are in “telomerase-extendible” or “telomerase-non-extendible” states. We propose that these two states are instead structurally and temporally distinct substrates for telomerase, generated by two different processes (fork collapse vs . completion of DNA replication). We also show that replication fork collapse at telomeres is kept in check by a telomere-dedicated Cdc13/Stn1/Ten1 complex in collaboration with the canonical RPA complex, indicating that these two complexes bind single-stranded DNA exposed at the replication fork to facilitate replisome progression through duplex telomeric DNA. Although failures during DNA replication are often genotoxic events, this represents an opposing example in which fork collapse has been co-opted to promote genome stability. Significance Statement In most eukaryotes, the termini of linear chromosomes are composed of arrays of short repeats that are continually replenished by the enzyme telomerase. If telomerase is unable to act, gradual loss of these terminal repeats results in an eventual block to cell division. Therefore, in cells that depend on continuous cell division, the mechanism(s) by which telomerase is directed to chromosome ends is tightly regulated. This study shows that in addition to the ends of fully replicated chromosomes, a second site of action for telomerase is generated when replication through duplex telomeric DNA is disrupted. These results suggest that the disparate response of telomerase to two temporally and structurally distinct substrates is a major determinant of telomere length homeostasis.

Yazarların özeti; kaynağından alınmıştır. Proceedings of the National Academy of Sciences, 2026 · DOI ↗