Abstract
Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. Replication stress, such as fork stalling and collapse, can arise at natural impediments present throughout the genome if not properly regulated. These impediments include telomeres, which contain repetitive DNA sequences and abundant DNA‐binding proteins. Due to such natures, telomeres are considered to be difficult to replicate. However, the mechanism of telomere replication remains elusive. In this report, we describe a genome‐wide study that identifies the Swi1Timeless protein as a critical factor to prevent repeat instability and recombination at telomeres. Loss of Swi1 causes telomere and subtelomere shortening in a telomerase‐independent manner. Our genetic studies suggest that heterochromatin and telomere‐binding proteins are not major impediments for telomere replication in the absence of Swi1. Instead, repetitive DNA sequences impair telomere integrity in swi1Δ mutant cells, leading to the loss of repeat DNAs. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase, silencing defects, and activation of the alternative lengthening of telomeres pathway (ALT) in telomerase‐negative cells. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also contribute to the understanding the mechanism of ALT in human cancers.
Highlights
Eukaryotic cells must accurately replicate their genetic information every cell cycle
Cells carry an array of complex mechanisms to deal with various obstacles found across the genome that can hamper DNA replication and cause DNA damage
We describe how Swi1, a Timeless-related protein in fission yeast, regulates efficient replication of telomeres, which are considered to be difficult to replicate due to the presence of repetitive DNA and telomere-binding proteins
Summary
Eukaryotic cells must accurately replicate their genetic information every cell cycle This process is challenged by the presence of natural impediments throughout the genome that can halt replisome progression, potentially causing genomic instability, a hallmark of cancer and other hereditary disorders [1,2,3,4]. The second group includes DNA secondary structures such as G quadruplexes, hairpins, and triplex DNA, which are often found at repetitive or palindromic DNA sequences [10,11,12,13,14,15] These RFBs present obstacles for DNA replication, the nature of these barriers and the mechanisms by which the cell ensures the smooth passage of the replisome through each RFB are not fully understood
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