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Daishi Yamakawa, Weizhen Jia, Hiroyasu Kidoya, Shoko Hosojima, Miku Torigata, Li Zhang, Nobuyuki Takakura
Vascular endothelial cells (ECs) isolated from tumors characteristically express certain genes. It has recently been suggested that tumor vessel normalization facilitates effective drug delivery into tumors; however, how tumor vessel normalization can be recognized on the basis of the molecules expressed by tumor ECs is not clearly defined. The degree of cell proliferation is an important indicator to characterize the condition of the ECs. Herein, we generated transgenic mice expressing enhanced green fluorescent protein (EGFP) under the transcriptional control of the DNA replication factor partner of Sld5-1 (PSF1; official name GINS1) promoter to assess whether active ECs can be distinguished from dormant ECs...
April 2, 2018: American Journal of Pathology
Ewa Szwajczak, Iwona J Fijalkowska, Catherine Suski
Eukaryotic DNA replication is performed by high-fidelity multi-subunit replicative B-family DNA polymerases (Pols) α, δ and ɛ. Those complexes are composed of catalytic and accessory subunits and organized in multicomplex machinery: the replisome. The fourth B-family member, DNA polymerase zeta (Pol ζ), is responsible for a large portion of mutagenesis in eukaryotic cells. Two forms of Pol ζ have been identified, a hetero-dimeric (Pol ζ2 ) and a hetero-tetrameric (Pol ζ4 ) ones and recent data have demonstrated that Pol ζ4 is responsible for damage-induced mutagenesis...
November 2017: Molecular Microbiology
Mari Yoshida, Yukichi Ishioka, Takamasa Ozawa, Hirohisa Okuyama, Motofumi Iguchi, Takeshi Ota, Takaomi Ito, Morio Nagira, Atsushi Morita, Hidekazu Tanaka, Hisamichi Naito, Hiroyasu Kidoya, Nobuyuki Takakura
Partner of sld five 1 (PSF1) is an evolutionary conserved DNA replication factor involved in DNA replication in lower species, which is strongly expressed in normal stem cell populations and progenitor cell populations. Recently, we have investigated PSF1 functions in cancer cells and found that PSF1 plays a significant role in tumour growth. These findings provide initial evidence for the potential of PSF1 as a therapeutic target. Here, we reveal that PSF1 contains an immunogenic epitope suitable for an antitumour vaccine...
September 11, 2017: Scientific Reports
Julien Cottineau, Molly C Kottemann, Francis P Lach, Young-Hoon Kang, Frédéric Vély, Elissa K Deenick, Tomi Lazarov, Laure Gineau, Yi Wang, Andrea Farina, Marie Chansel, Lazaro Lorenzo, Christelle Piperoglou, Cindy S Ma, Patrick Nitschke, Aziz Belkadi, Yuval Itan, Bertrand Boisson, Fabienne Jabot-Hanin, Capucine Picard, Jacinta Bustamante, Céline Eidenschenk, Soraya Boucherit, Nathalie Aladjidi, Didier Lacombe, Pascal Barat, Waseem Qasim, Jane A Hurst, Andrew J Pollard, Holm H Uhlig, Claire Fieschi, Jean Michon, Vladimir P Bermudez, Laurent Abel, Jean-Pierre de Villartay, Frédéric Geissmann, Stuart G Tangye, Jerard Hurwitz, Eric Vivier, Jean-Laurent Casanova, Agata Smogorzewska, Emmanuelle Jouanguy
Inborn errors of DNA repair or replication underlie a variety of clinical phenotypes. We studied 5 patients from 4 kindreds, all of whom displayed intrauterine growth retardation, chronic neutropenia, and NK cell deficiency. Four of the 5 patients also had postnatal growth retardation. The association of neutropenia and NK cell deficiency, which is unusual among primary immunodeficiencies and bone marrow failures, was due to a blockade in the bone marrow and was mildly symptomatic. We discovered compound heterozygous rare mutations in Go-Ichi-Ni-San (GINS) complex subunit 1 (GINS1, also known as PSF1) in the 5 patients...
May 1, 2017: Journal of Clinical Investigation
Marta Carroni, Matteo De March, Barbara Medagli, Ivet Krastanova, Ian A Taylor, Heinz Amenitsch, Hiroyuchi Araki, Francesca M Pisani, Ardan Patwardhan, Silvia Onesti
GINS is a key component of eukaryotic replicative forks and is composed of four subunits (Sld5, Psf1, Psf2, Psf3). To explain the discrepancy between structural data from crystallography and electron microscopy (EM), we show that GINS is a compact tetramer in solution as observed in crystal structures, but also forms a double-tetrameric population, detectable by EM. This may represent an intermediate step towards the assembly of two replicative helicase complexes at origins, moving in opposite directions within the replication bubble...
January 10, 2017: Scientific Reports
Ryu Kanzaki, Hisamichi Naito, Kazuyoshi Kise, Kazuhiro Takara, Daisuke Eino, Masato Minami, Yasushi Shintani, Soichiro Funaki, Tomohiro Kawamura, Toru Kimura, Meinoshin Okumura, Nobuyuki Takakura
BACKGROUND: PSF1 (Partner of SLD Five 1) is an evolutionarily conserved DNA replication factor that is part of the GINS (Go, Ichi, Nii, and San) complex . The objective of this study was to evaluate the relationship between PSF1 expression and prognosis in patients with non-small cell lung cancer (NSCLC) treated with surgery following preoperative chemotherapy or chemoradiotherapy. METHODS: Sixty-nine patients with NSCLC treated with surgery following preoperative chemotherapy or chemoradiotherapy who did not achieve pathologic complete response were enrolled...
November 2016: Annals of Surgical Oncology
Shan-shan Yue, Lai-xin Xia
The synaptonemal complex (SC) is a huge structure which assembles between the homologous chromosomes during meiotic prophase I. Drosophila germ cell-specific nucleoprotein C(2)M clustering at chromosomes can induce SC formation. To further study the molecular function and mechanism of C(2)M in meiosis, we constructed a bait vector for C(2)M and used the yeast two-hybrid system to identify C(2)M interacting proteins. Forty interacting proteins were obtained, including many DNA and histone binding proteins, ATP synthases and transcription factors...
November 2015: Yi Chuan, Hereditas
Yinglu Han, Zhi-Yuan Gong, Nobuyuki Takakura
Hematopoietic stem cells (HSCs) can survive long-term in a state of dormancy. Little is known about how histone deacetylase inhibitors (HDACi) affect HSC kinetics. Here, we use trichostatin A (TSA), a histone deacetylase inhibitor, to enforce histone acetylation and show that this suppresses cell cycle entry by dormant HSCs. Previously, we found that haploinsufficiency of PSF1, a DNA replication factor, led to attenuation of the bone marrow (BM) HSC pool size and lack of acute proliferation after 5-FU ablation...
June 10, 2015: Experimental Cell Research
Marta Garbacz, Hiroyuki Araki, Krzysztof Flis, Anna Bebenek, Anna E Zawada, Piotr Jonczyk, Karolina Makiela-Dzbenska, Iwona J Fijalkowska
DNA polymerase epsilon interacts with the CMG (Cdc45-MCM-GINS) complex by Dpb2p, the non-catalytic subunit of DNA polymerase epsilon. It is postulated that CMG is responsible for targeting of Pol ɛ to the leading strand. We isolated a mutator dpb2-100 allele which encodes the mutant form of Dpb2p. We showed previously that Dpb2-100p has impaired interactions with Pol2p, the catalytic subunit of Pol ɛ. Here, we present that Dpb2-100p has strongly impaired interaction with the Psf1 and Psf3 subunits of the GINS complex...
May 2015: DNA Repair
Xiaoli Sun, Wu Sui, Miaoling Huang, Yeli Wang, Yuanjie Xuan, Zaiqiu Wang
BACKGROUND: Partner of Sld five 3 (PSF3) is a member of the evolutionarily conserved heterotetrameric complex "Go-Ichi-Ni-San" (GINS), which consists of SLD5, PSF1, PSF2, and PSF3. Previous studies have suggested that some GINS complex members are upregulated in cancer, but the status of PSF3 expression in colorectal cancer has not been investigated. METHODS: We investigated the status of PSF3 expression in 137 consecutive resected colorectal caners by quantitative reverse-transcription polymerase chain reaction...
2014: Diagnostic Pathology
H Tahara, H Naito, K Kise, T Wakabayashi, K Kamoi, K Okihara, A Yanagisawa, Y Nakai, N Nonomura, E Morii, T Miki, N Takakura
BACKGROUND: Partner of SLD5 1 (PSF1) is an evolutionarily conserved DNA replication factor. Previous studies have suggested that transcriptional activity of the PSF1 gene correlated with malignancy of cancer cells. The objective of the current study was to evaluate the relationship between PSF1 expression and the clinical features of prostate cancer. METHODS: We determined the expression of PSF1 in 120 needle biopsy samples of prostate cancer by immunohistochemistry...
March 2015: Prostate Cancer and Prostatic Diseases
Jingyao Zhang, Qifei Wu, Zhe Wang, Yong Zhang, Guangjian Zhang, Junke Fu, Chang Liu
Partner of sld five 1 (PSF1) is a member of the heterotetrameric complex termed GINS. Previous studies have shown that PSF1 is unregulated in several cancer and associated with tumor malignant characters. However, the effects of PSF1 in lung cancer are still unclear. The goal of this study was to investigate the effects of PSF1 on the proliferation capacities of lung cancer. To start with, expression of PSF1 in 22 human lung cancer samples and adjacent non-tumor samples were detected by real-time RT-PCR and Western blotting...
March 2015: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Zhi-Yuan Gong, Hiroyasu Kidoya, Tomomi Mohri, Yinglu Han, Nobuyuki Takakura
SLD5 is a member of the GINS complex composed of PSF1, PSF2, PSF3 and SLD5, playing a critical role in the formation of the DNA replication fork with CDC45 in yeast. Previously, we had isolated a PSF1 orthologue from a murine hematopoietic stem cell DNA library and were then able to identify orthologues of all the other GINS members by the yeast two hybrid approach using PSF1 as the bait. These GINS orthologues may also function in DNA replication in mammalian cells because they form tetrameric complexes as observed in yeast, and gene deletion mutants of both PSF1 and SLD5 result in a lack of epiblast proliferation and early embryonic lethality...
2014: PloS One
Lance D Langston, Dan Zhang, Olga Yurieva, Roxana E Georgescu, Jeff Finkelstein, Nina Y Yao, Chiara Indiani, Mike E O'Donnell
DNA replication in eukaryotes is asymmetric, with separate DNA polymerases (Pol) dedicated to bulk synthesis of the leading and lagging strands. Pol α/primase initiates primers on both strands that are extended by Pol ε on the leading strand and by Pol δ on the lagging strand. The CMG (Cdc45-MCM-GINS) helicase surrounds the leading strand and is proposed to recruit Pol ε for leading-strand synthesis, but to date a direct interaction between CMG and Pol ε has not been demonstrated. While purifying CMG helicase overexpressed in yeast, we detected a functional complex between CMG and native Pol ε...
October 28, 2014: Proceedings of the National Academy of Sciences of the United States of America
Lei Zhou, Xue-jun Sun, Chang Liu, Qi-fei Wu, Ming-hui Tai, Ji-chao Wei, Lei Lei, Fan-di Meng, Kai Qu, Jia Xu
BACKGROUND: PSF1 is a subunit of the GINS complex which is essential for establishment of DNA replication forks, and the progression of the replisome. Previous studies have shown a close relationship between PSF1 and cell cycle in the proliferation of immature cells as well as tumors. The purpose of this study was to measure PSF1 expression in hepatocellular carcinoma (HCC) tissues, and determine the effects of down-regulation of PSF1 expression on growth of cancer cells, the cell cycle, apoptosis and cell invasiveness...
February 24, 2015: International Journal of Biological Markers
Ewa Grabowska, Urszula Wronska, Milena Denkiewicz, Malgorzata Jaszczur, Aleksandra Respondek, Malgorzata Alabrudzinska, Catherine Suski, Karolina Makiela-Dzbenska, Piotr Jonczyk, Iwona J Fijalkowska
The role of replicative DNA polymerases in ensuring genome stability is intensively studied, but the role of other components of the replisome is still not fully understood. One of such component is the GINS complex (comprising the Psf1, Psf2, Psf3 and Sld5 subunits), which participates in both initiation and elongation of DNA replication. Until now, the understanding of the physiological role of GINS mostly originated from biochemical studies. In this article, we present genetic evidence for an essential role of GINS in the maintenance of replication fidelity in Saccharomyces cerevisiae...
May 2014: Molecular Microbiology
Tomomi Mohri, Masaya Ueno, Yumi Nagahama, Zhi-Yuan Gong, Masahide Asano, Hiroko Oshima, Masanobu Oshima, Yasushi Fujio, Nobuyuki Takakura
SLD5 forms a GINS complex with PSF1, PSF2 and PSF3, which is essential for the initiation of DNA replication in lower eukaryotes. Although these components are conserved in mammals, their biological function is unclear. We show here that targeted disruption of SLD5 in mice causes a defect in cell proliferation in the inner cell mass, resulting in embryonic lethality at the peri-implantation stage, indicating that SLD5 is essential for embryogenesis. Moreover, this phenotype of SLD5 mutant mice is quite similar compared with that of PSF1 mutant mice...
2013: PloS One
Sugopa Sengupta, Frederick van Deursen, Giacomo de Piccoli, Karim Labib
BACKGROUND: The eukaryotic replisome is a critical determinant of genome integrity with a complex structure that remains poorly characterized. A central unresolved issue is how the Cdc45-MCM-GINS helicase is linked to DNA polymerase epsilon, which synthesizes the leading strand at replication forks and is an important focus of regulation. RESULTS: Here, we use budding yeast to show that a conserved amino-terminal domain of the Dpb2 subunit of Pol ε (Dpb2NT) interacts with the Psf1 component of GINS, via the unique "B domain" of the latter that is dispensable for assembly of the GINS complex but is essential for replication initiation...
April 8, 2013: Current Biology: CB
Takahiro Matsui, Yumi Kinugasa, Hidekazu Tahara, Yuzuru Kanakura, Nobuyuki Takakura
Cancer recurrence has been suggested to be induced by residual cancer-initiating cells (CICs) or cancer stem cells (CSCs) after chemotherapy. Moreover, it is possible that CICs/CSCs acquire more aggressive behavior after therapy as shown by invasion and metastasis. In the cancer microenvironment, CICs/CSCs may localize in a specific area, the so-called stem cell niche, and isolation of this niche is important to elucidate the molecular mechanism of how CICs/CSCs acquire malignancy. We analyzed whether CICs acquire drug resistance after cancer drug treatment in a tumor cell allograft model in which we could identify and isolate living CICs by detecting a higher level of transcriptional activity of the PSF1 gene promoter...
May 2013: American Journal of Pathology
Ji-zhi Wen, Xiao-yan Han, Bo Wei, Shi Zhang, Hong-bo Wei
OBJECTIVE: To detect the expression of PSF1 (partner of Sld five 1) in colon cancer specimens, and to explore the effect of RNA interference targeting PSF1 on the proliferation of colon cancer cells and its mechanism. METHODS: Expression level of PSF1 protein in colon cancer specimens was detected by Western blot in 40 patients with colon cancer from May 2004 to December 2006. The short hairpin RNA (shRNA) plasmid targeting PSF1 was transfected into LOVO, HT-29 and HCT116 cells with liposome, then the expression level of PSF1 protein was measured by Western blot, the effect of PSF1 shRNA plasmid transfection on cell proliferation by MTT assay, anchorage-independent growth by soft agar colomy-formation assay, and PSF2, PSF3 and SLD5 mRNA expression by quantitative reverse transcription polymerase chain reaction...
January 2013: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
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