Telomere Replication: Solving Multiple End Replication Problems

Abstract

Eukaryotic genomes are highly complex and divided into linear chromosomes that require end protection from unwarranted fusions, recombination, and degradation in order to maintain genomic stability. This is accomplished through the conserved specialized nucleoprotein structure of telomeres. Due to the repetitive nature of telomeric DNA, and the unusual terminal structure, namely a protruding single stranded 3′ DNA end, completing telomeric DNA replication in a timely and efficient manner is a challenge. For example, the end replication problem causes a progressive shortening of telomeric DNA at each round of DNA replication, thus telomeres eventually lose their protective capacity. This phenomenon is counteracted by the recruitment and the activation at telomeres of the specialized reverse transcriptase telomerase. Despite the importance of telomerase in providing a mechanism for complete replication of telomeric ends, the majority of telomere replication is in fact carried out by the conventional DNA replication machinery. There is significant evidence demonstrating that progression of replication forks is hampered at chromosomal ends due to telomeric sequences prone to form secondary structures, tightly DNA-bound proteins, and the heterochromatic nature of telomeres. The telomeric loop (t-loop) formed by invasion of the 3′-end into telomeric duplex sequences may also impede the passage of replication fork. Replication fork stalling can lead to fork collapse and DNA breaks, a major cause of genomic instability triggered notably by unwanted repair events. Moreover, at chromosomal ends, unreplicated DNA distal to a stalled fork cannot be rescued by a fork coming from the opposite direction. This highlights the importance of the multiple mechanisms involved in overcoming fork progression obstacles at telomeres. Consequently, numerous factors participate in efficient telomeric DNA duplication by preventing replication fork stalling or promoting the restart of a stalled replication fork at telomeres. In this review, we will discuss difficulties associated with the passage of the replication fork through telomeres in both fission and budding yeasts as well as mammals, highlighting conserved mechanisms implicated in maintaining telomere integrity during replication, thus preserving a stable genome.

Plasticity, pleiotropy and fitness trade‐offs in Arabidopsis genotypes with different telomere lengths

“…To assess how any deviation away from the wild type telomere length impacted the phenotypes, we determined the absolute value of average difference of phenotypes for all genotypes relative to the Col-0 wild type. We applied the following transformation to all individuals: [1] We first calculated the mean trait value for Col-0 for each phenotype in each of the three treatments to generate a matrix of wild type phenotypes. [2] We then estimated the difference from the wild type by subtracting the observed phenotypic value for each individual from the mean value for Col-0 in the appropriate treatment.…”

Reconstitution of a telomeric replicon organized by CST

“…Numerous studies have found that telomeric DNA presents difficulties for replication, including problems with replication fork stalling (reviewed in ref. 32 ). Replication of both the ds and ssDNA regions of telomeres could contribute to these difficulties.…”

Exploring the Structures and Functions of Macromolecular SLX4-Nuclease Complexes in Genome Stability

“…As alluded to above, SLX4 has an important role in maintaining telomere length and stability. This is not surprising, given that branched DNA structures are expected to occur frequently in telomeres because of their highly repetitive DNA sequence (for reviews, see Maestroni et al, 2017;Bonnell et al, 2021). Telomeres are essential nucleoprotein structures that form a protective cap for the terminal segments of linear chromosomes.…”