Proceedings of the National Academy of Sciences of the United States of AmericaOct 26, 2026

Natural DNA copying errors help control chromosome end length in normal yeast

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Updated Oct 27, 2026

Abstract

As much as 200 nucleotides can be added in a single cell division to newly collapsed replication forks in budding yeast.

Telomerase elongates a second substrate generated by replication fork collapse at a higher frequency than it does at fully replicated chromosome ends.
This newly identified substrate arises from spontaneous replication stress rather than the traditional single-stranded G-rich overhang.
The findings suggest that telomere length homeostasis is significantly influenced by the response of telomerase to replication fork collapse.
The traditional model of telomere length sensing is challenged, proposing instead that there are structurally distinct substrates for telomerase based on different DNA replication processes.
Replication fork collapse at telomeres is regulated by a specialized complex that works with the canonical RPA complex to stabilize single-stranded DNA.

Simplified

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. However, increasing evidence indicates that a second telomerase substrate is generated in response to replication stress as the replisome traverses duplex telomeric DNA. We show here that this second substrate, created by spontaneous replication fork collapse in wild-type budding yeast, is elongated by telomerase at a much higher frequency than fully replicated chromosome termini. Furthermore, as much as ~200 nucleotides can be added in a single cell division to newly collapsed forks, indicating that replication fork collapse and the subsequent response by telomerase is a major determinant of telomere length homeostasis. This challenges a long-standing model which posits a length-sensing mechanism that assesses individual telomeres to determine whether yeast chromosome ends are in "telomerase-extendible" versus "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 versus completion of DNA replication). We also show that 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 stabilize single-stranded DNA exposed at the replication fork. 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.

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Natural DNA copying errors help control chromosome end length in normal yeast

Abstract

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