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Human Timeless and Tipin stabilize replication forks and facilitate sister-chromatid cohesion
Journal article   Open access   Peer reviewed

Human Timeless and Tipin stabilize replication forks and facilitate sister-chromatid cohesion

Adam R Leman, Chiaki Noguchi, Candice Y Lee and Eishi Noguchi
Journal of cell science, v 123(Pt 5), pp 660-670
01 Mar 2010
DOI: https://doi.org/10.1242/jcs.057984
PMID: 20124417
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1242/jcs.057984View
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Abstract

Cell Cycle - genetics Immunoprecipitation Hydroxyurea - toxicity DNA Replication - drug effects Humans Intracellular Signaling Peptides and Proteins - metabolism Chromatids - metabolism Chromatin Immunoprecipitation Cell Cycle Proteins - genetics DEAD-box RNA Helicases - metabolism Nuclear Proteins - genetics Intracellular Signaling Peptides and Proteins - genetics Cell Line Chromosomal Proteins, Non-Histone - metabolism Cell Cycle Proteins - metabolism Nuclear Proteins - metabolism Electrophoresis, Gel, Pulsed-Field Carrier Proteins - genetics Carrier Proteins - metabolism Fluorescent Antibody Technique Cell Cycle - physiology DNA Replication - genetics Protein Binding RNA, Small Interfering HeLa Cells
The Timeless-Tipin protein complex has been reported to be important for replication checkpoint and normal DNA replication processes. However, the precise mechanisms by which Timeless-Tipin preserves genomic integrity are largely unclear. Here, we describe the roles of Timeless-Tipin in replication fork stabilization and sister chromatid cohesion. We show in human cells that Timeless is recruited to replication origin regions and dissociate from them as replication proceeds. Cdc45, which is known to be required for replication fork progression, shows similar patterns of origin association to those of Timeless. Depletion of Timeless-Tipin causes chromosome fragmentation and defects in damage repair in response to fork collapse, suggesting that it is required for replication fork maintenance under stress. We also demonstrate that depletion of Timeless-Tipin impairs sister chromatid cohesion and causes a defect in mitotic progression. Consistently, Timeless-Tipin co-purifies with cohesin subunits and is required for their stable association with chromatin during S phase. Timeless associates with the cohesion-promoting DNA helicase ChlR1, which, when overexpressed, partially alleviates the cohesion defect of cells depleted of Timeless-Tipin. These results suggest that Timeless-Tipin functions as a replication fork stabilizer that couples DNA replication with sister chromatid cohesion established at replication forks.

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110 citations in Web of Science
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Cell Biology
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