Abstract
Genomic instability associated with DNA replication stress is linked to cancer and genetic pathologies in humans. If not properly regulated, replication stress, such as fork stalling and collapse, can be induced at natural replication impediments present throughout the genome. The fork protection complex (FPC) is thought to play a critical role in stabilizing stalled replication forks at several known replication barriers including eukaryotic rDNA genes and the fission yeast mating-type locus. However, little is known about the role of the FPC at other natural impediments including telomeres. Telomeres are considered to be difficult to replicate due to the presence of repetitive GT-rich sequences and telomere-binding proteins. However, the regulatory mechanism that ensures telomere replication is not fully understood. Here, we report the role of the fission yeast Swi1Timeless, a subunit of the FPC, in telomere replication. Loss of Swi1 causes telomere shortening in a telomerase-independent manner. Our epistasis analyses 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 DNA. In the absence of Swi1, telomere shortening is accompanied with an increased recruitment of Rad52 recombinase and more frequent amplification of telomere/subtelomeres, reminiscent of tumor cells that utilize the alternative lengthening of telomeres pathway (ALT) to maintain telomeres. These results suggest that Swi1 ensures telomere replication by suppressing recombination and repeat instability at telomeres. Our studies may also be relevant in understanding the potential role of Swi1Timeless in regulation of telomere stability in cancer cells.
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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