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Analysis of institutional authors

Hazen De San Juan, M JoseAuthorMartin Sanchez CAuthorPerez Martin JmAuthor

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September 22, 2015
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Disruption of the mevalonate pathway induces dNTP depletion and DNA damage

Publicated to:BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS. 1851 (9): 1240-1253 - 2015-09-01 1851(9), DOI: 10.1016/j.bbalip.2015.06.001

Authors: Martin Sanchez, Covadonga; Perez Martin, Jose Manuel; Jin, Jong-Sik; Davalos, Alberto; Zhang, Wei; de la Pena, Gema; Martinez-Botas, Javier; Rodriguez-Acebes, Sara; Suarez, Yajaira; Jose Hazen, Maria; Gomez-Coronado, Diego; Busto, Rebeca; Cheng, Yung-Chi; Lasuncion, Miguel A

Affiliations

Chonbuk Natl Univ, Coll Environm & Bioresource Sci, Dept Oriental Med Resources, Jeonju, Jeonbuk, South Korea - Author
CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Spain - Author
Departamento de Biología, Facultad de Ciencias, Universidad Autónoma de Madrid, Madrid, Spain - Author
Department of Oriental Medicine Resources, College of Environmental and Bioresource Sciences, Chonbuk National University, Jeonju, Jeonbuk, South Korea - Author
Department of Pharmacology, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, United States - Author
DNA Replication Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain - Author
Facultad de Ciencias Sociales y Educación, Universidad Camilo José Cela, 28692 Villanueva de la Cañada, Madrid, Spain - Author
IMDEA Food, Lab Funct Foods, Madrid 28036, Spain - Author
Inst Salud Carlos III ISCIII, CIBER Fisiopatol Obesidad & Nutr CIBEROBN, Madrid, Spain - Author
IRyCIS, Serv Bioquim Invest, Hosp Univ Ramon & Cajal, Madrid 28034, Spain - Author
Laboratory of Functional Foods, IMDEA-Food, Madrid, Spain - Author
Macau Univ Sci & Technol, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China - Author
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Pathology, Yale University School of Medicine, New Haven, CT, United States - Author
Servicio de Bioquímica-Investigación, Hospital Universitario Ramón y Cajal, IRyCIS, Madrid, Spain - Author
Spanish Natl Canc Res Ctr CNIO, DNA Replicat Grp, Madrid 28029, Spain - Author
State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macau - Author
Univ Autonoma Madrid, Fac Ciencias, Dept Biol, E-28049 Madrid, Spain - Author
Yale Univ, Sch Med, Program Integrat Cell Signaling & Neurobiol Metab, Sect Comparat Med,Dept Pathol, New Haven, CT 06520 USA - Author
Yale Univ, Sch Med, Sect Med Oncol, Dept Pharmacol, New Haven, CT 06520 USA - Author
Yale Univ, Sch Med, Vasc Biol & Therapeut Program, New Haven, CT 06520 USA - Author
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Abstract

The mevalonate pathway is tightly linked to cell division. Mevalonate derived non-sterol isoprenoids and cholesterol are essential for cell cycle progression and mitosis completion respectively. In the present work, we studied the effects of fluoromevalonate, a competitive inhibitor of mevalonate diphosphate decarboxylase, on cell proliferation and cell cycle progression in both HL-60 and MOLT-4 cells. This enzyme catalyzes the synthesis of isopentenyl diphosphate, the first isoprenoid in the cholesterol biosynthesis pathway, consuming ATP at the same time. Inhibition of mevalonate diphosphate decarboxylase was followed by a rapid accumulation of mevalonate diphosphate and the reduction of ATP concentrations, while the cell content of cholesterol was barely affected. Strikingly, mevalonate diphosphate decarboxylase inhibition also resulted in the depletion of dNTP pools, which has never been reported before. These effects were accompanied by inhibition of cell proliferation and cell cycle arrest at S phase, together with the appearance of ?-H2AX foci and Chk1 activation. Inhibition of Chk1 in cells treated with fluoromevalonate resulted in premature entry into mitosis and massive cell death, indicating that the inhibition of mevalonate diphosphate decarboxylase triggered a DNA damage response. Notably, the supply of exogenously deoxyribonucleosides abolished ?-H2AX formation and prevented the effects of mevalonate diphosphate decarboxylase inhibition on DNA replication and cell growth. The results indicate that dNTP pool depletion caused by mevalonate diphosphate decarboxylase inhibition hampered DNA replication with subsequent DNA damage, which may have important consequences for replication stress and genomic instability. Copyright © 2015 Elsevier B.V. All rights reserved.

Keywords

cholesteroldeoxyribonucleotidesdna damagefluoromevalonate5-diphosphomevalonic acidAdenosine triphosphateArticleCarboxy-lyasesCarboxylyaseCell cycle checkpointsCell cycle progressionCell divisionCell growthCell line, tumorCell proliferationCheckpoint kinase 1Chek1 protein, humanCholesterolCholesterol synthesisControlled studyDeoxyribonucleoside triphosphateDeoxyribonucleosidesDeoxyribonucleotidesDna contentDna damageDna replicationEnzyme activationEnzyme inhibitionEnzyme mechanismFluoromevalonateGamma h2axGene expression regulationGenomic instabilityH2ax protein, humanHalogenationHemiterpenesHistone h2axHistonesHl 60 cell lineHl-60 cellsHumanHuman cellHumansIsopentenyl diphosphateIsopentenyl pyrophosphateIsoprenoidLymphocytesMevalonateMevalonate diphosphate decarboxylaseMevalonic acidMitosisOrganophosphorus compoundsPriority journalProtein kinasesPyrophosphomevalonate decarboxylaseRna, small interferingS phase cell cycle checkpointSignal transductionUnclassified drug

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2015, it was in position 13/72, thus managing to position itself as a Q1 (Primer Cuartil), in the category Biophysics.

From a relative perspective, and based on the normalized impact indicator calculated from the Field Citation Ratio (FCR) of the Dimensions source, it yields a value of: 1.4, which indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: Dimensions Jul 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-07-06, the following number of citations:

  • WoS: 13
  • Scopus: 14
  • Europe PMC: 9
  • Google Scholar: 15

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-06:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 40.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 41 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 3.
  • The number of mentions on the social network X (formerly Twitter): 6 (Altmetric).

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: China; Macao; Republic of Korea; United States of America.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (MARTIN SANCHEZ, CAROLINA) .