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Journal article
Swi1(Timeless) Prevents Repeat Instability at Fission Yeast Telomeres
PLoS genetics, v 12(3), 1005943
01 Mar 2016
PMID: 26990647
Featured in Collection : UN Sustainable Development Goals @ Drexel
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 Swi1(Timeless), 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 swi1 Delta 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 Swi1(Timeless) in regulation of telomere stability in cancer cells.
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Details
- Title
- Swi1(Timeless) Prevents Repeat Instability at Fission Yeast Telomeres
- Creators
- Mariana C. Gadaleta - Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USAMukund M. Das - Drexel Univ, Coll Med, Dept Biochem & Mol Biol, Philadelphia, PA 19104 USAHideki Tanizawa - Wistar Inst Anat & Biol, Gene Express & Regulat Program, 3601 Spruce St, Philadelphia, PA 19104 USAYa-Ting Chang - University of Illinois ChicagoKen-ichi Noma - Wistar Inst Anat & Biol, Gene Express & Regulat Program, 3601 Spruce St, Philadelphia, PA 19104 USAToru M. Nakamura - Univ Illinois, Coll Med, Dept Biochem & Mol Genet, Chicago, IL USAEishi Noguchi - Drexel University, Biochemistry and Molecular Biology
- Publication Details
- PLoS genetics, v 12(3), 1005943
- Publisher
- Public Library Science
- Number of pages
- 28
- Grant note
- Aging Initiative at Drexel University College of Medicine DP2OD004348 / OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA GM077604; GM078253; DP2-OD004348 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA P30CA010815 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R01GM078253 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) G. Harold & Leila Y. Mathers Charitable Foundation P30CA010815 / Cancer Center Support Grant (CCSG)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology
- Web of Science ID
- WOS:000373268900048
- Scopus ID
- 2-s2.0-84962429242
- Other Identifier
- 991019167919204721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity