Swi1Timeless Prevents Repeat Instability at Fission Yeast Telomeres

Autor: Eishi Noguchi, Ken-ichi Noma, Hideki Tanizawa, Mukund M. Das, Ya Ting Chang, Mariana C. Gadaleta, Toru Nakamura
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Gene Expression
Cell Cycle Proteins
Yeast and Fungal Models
Eukaryotic DNA replication
Biochemistry
Electrophoretic Blotting
Schizosaccharomyces Pombe
0302 clinical medicine
Heterochromatin
Macromolecular Structure Analysis
Telomere Shortening
Genetics (clinical)
Gel Electrophoresis
Genetics
Telomere-binding protein
Chromosome Biology
Telomere
Chromatin
DNA-Binding Proteins
Nucleic acids
Telomeres
030220 oncology & carcinogenesis
Microsatellite Instability
Epigenetics
Research Article
DNA Replication
Chromosome Structure and Function
Protein Structure
lcsh:QH426-470
Telomere-Binding Proteins
Molecular Probe Techniques
Biology
Research and Analysis Methods
Genomic Instability
Chromosomes
Electrophoretic Techniques
03 medical and health sciences
Model Organisms
Telomere Homeostasis
Minichromosome maintenance
Control of chromosome duplication
Schizosaccharomyces
Humans
Molecular Biology Techniques
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Repetitive Sequences
Nucleic Acid
Organisms
Fungi
DNA replication
Biology and Life Sciences
Proteins
Cell Biology
DNA
Yeast
Rad52 DNA Repair and Recombination Protein
lcsh:Genetics
030104 developmental biology
Genetic Loci
DNA damage
Origin recognition complex
Schizosaccharomyces pombe Proteins
Protein Structure Networks
Southern Blot
Zdroj: PLoS Genetics
PLoS Genetics, Vol 12, Iss 3, p e1005943 (2016)
ISSN: 1553-7404
DOI: 10.1371/journal.pgen.1005943
Popis: 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.
Author Summary In every round of the cell cycle, cells must accurately replicate their full genetic information. This process is highly regulated, as defects during DNA replication cause genomic instability, leading to various genetic disorders including cancers. To thwart these problems, 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. Understanding how these mechanisms are regulated and orchestrated is of paramount importance in the field. In this report, 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. We show that Swi1 prevents telomere damage and maintains telomere length by protecting integrity of telomeric repeats. Swi1-mediated telomere maintenance is independent of telomerase activity, and loss of Swi1 causes hyper-activation of recombination-based telomere maintenance, which generates heterogeneous telomeres. Similar telomerase-independent and recombination-dependent mechanism is utilized by approximately 15% of human cancers, linking telomere replication defects with cancer development. Thus, our study may be relevant in understanding the role of telomere replication defects in the development of cancers in humans.
Databáze: OpenAIRE
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