A Gospodinov

A Rogeuv

BC Baguley

BJ Monahan

C Carvalho

CJ Hogan

D Helmlinger

Ee Sin Chen

FJ Sharom

FK Khasanov

G Brea-Calvo

G Szakács

H Kitano

H Raji

H van Attikum

JC Wang

Juan Mata

K Dawson

KA Conklin

Kenichi Sajiki

Kim Kiat Lim

L Xia

M Kawamukai

M Pajic

M Tokarska-Schlattner

Ming Yi Tang

Mitsuhiro Yanagida

MS Szalay

RA Bilardi

Ru Jun Eng

S Cavero

SJ Dixon

TR Singh

V Hanušová

Y Bao

Y Ma

Y Pommier

Zoey Tay

PLoS ONE

PubMed

Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast Schizosaccharomyces pombe. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance

Directory of Open Access Journals

Cellular robustness conferred by genetic crosstalk underlies resistance against chemotherapeutic drug doxorubicin in fission yeast.

<div><p>Doxorubicin is an anthracycline antibiotic that is among one of the most commonly used chemotherapeutic agents in the clinical setting. The usage of doxorubicin is faced with many problems including severe side effects and chemoresistance. To overcome these challenges, it is important to gain an understanding of the underlying molecular mechanisms with regards to the mode of action of doxorubicin. To facilitate this aim, we identified the genes that are required for doxorubicin resistance in the fission yeast <em>Schizosaccharomyces pombe</em>. We further demonstrated interplay between factors controlling various aspects of chromosome metabolism, mitochondrial respiration and membrane transport. In the nucleus we observed that the subunits of the Ino80, RSC, and SAGA complexes function in the similar epistatic group that shares significant overlap with the homologous recombination genes. However, these factors generally act in synergistic manner with the chromosome segregation regulator DASH complex proteins, possibly forming two major arms for regulating doxorubicin resistance in the nucleus. Simultaneous disruption of genes function in membrane efflux transport or the mitochondrial respiratory chain integrity in the mutants defective in either Ino80 or HR function resulted in cumulative upregulation of drug-specific growth defects, suggesting a rewiring of pathways that synergize only when the cells is exposed to the cytotoxic stress. Taken together, our work not only identified factors that are required for survival of the cells in the presence of doxorubicin but has further demonstrated that an extensive molecular crosstalk exists between these factors to robustly confer doxorubicin resistance.</p> </div

Zoey Tay (276989)

Ru Jun Eng (276990)

Kenichi Sajiki (276991)

Kim Kiat Lim (276992)

Ming Yi Tang (276993)

Mitsuhiro Yanagida (214514)

Ee Sin Chen (273621)

The Francis Crick Institute

Cellular Robustness Conferred by Genetic Crosstalk Underlies Resistance against Chemotherapeutic Drug Doxorubicin in Fission Yeast

Tay Zoey

Eng Ru Jun

Sajiki Kenichi

Lim Kim Kiat

Tang Ming Yi

Yanagida Mitsuhiro

Chen Ee Sin

Public Library of Science (PLOS)

Crossref

A new recombinational DNA repair gene from Schizosaccharomyces pombe with homology to Escherichia coli RecA.

Alterations in myocardial energy metabolism induced by anti-cancer drug doxorubicin.

Biosynthesis and bioproduction of coenzyme Q10 by yeasts and other organisms.

Bous ˇova ´I ,S k a ´lova ´ L

Cellular roles of DNA topoisomerases: A molecular perspective.

Chromatin remodeling in DNA double-stranded break repair.

Coenzyme q10 for prevention of anthracycline-induced cytotoxicity.

Conservation and rewiring of functional modules revealed by an epistasis map in fission yeast.

Distinct roles of SWR1 and INO80 chromatin remodeling complexes at chromosomal double-stranded breaks.

DNA topoisomerases and their poisoning by anticancer and antibacterial drugs.

Double-strand break repair and homologous recombination in Schizosaccharomyces pombe.

Doxorubicin: The good, the bad and the ugly effect.

Fission yeast Iec1-Ino80-mediated nucleosome eviction regulates nucleotide and phosphate metabolism.

Fission yeast SWI/SNF and RSC complexes show compositional and functional differences from budding yeast.

Genome-wide screening for genes associated with FK506 sensitivity in fission yeast.

Identification of genes required for protection from doxorubicin by a genome-wide screen in Saccharomyces cerevisiae.

Loss of regulators of vacuolar ATPase function and ceramide synthesis results in multidrug sensitivity in Schizosaccharomyces pombe.

Mammalian Ino80 mediates double-stranded break repair through its role in DNA end strand resection.

MHF1-MHF2, a histone-fold-containing protein complex, participates in the Fanconi anemia pathway via FANCM.

Moderate increase in Mdr1a/1b expression causes in vivo resistance to doxorubicin in a mouse model for hereditary breast cancer.

Multidrug resistance in cancer.

Processing of anthracycline-DNA adducts via DNA replication and interstrand crosslink repair pathways.

Recent attempts at RNAi-mediated P-glycoprotein downregulation for reversal of multidrug resistance in cancer. Med Res Rev doi 10.1002/med.20244.

Robustness of cellular functions.

Rodrı ´guez-Herna ´ndez A, Ferna ´ndez-Ayala DJ, Navas P, Sa ´nchez-Alca ´zar JA

Stressinduced rearrangements of cellular networks: consequences for protection and drug design.

Targeting multidrug resistance in cancer.

The P-glyoprotein multidrug transporter.

The S. pombe SAGA complex controls the switch from proliferation to sexual differentiation through the opposing roles of its subunits

Towards a theory of biological robustness.

Yates JR 3 rd, He X

https://figshare.com/articles/Cellular_Robustness_Conferred_by_Genetic_Crosstalk_Underlies_Resistance_against_Chemotherapeutic_Drug_Doxorubicin_in_Fission_Yeast__/154310

Cellular Robustness Conferred by Genetic Crosstalk Underlies Resistance against Chemotherapeutic Drug Doxorubicin in Fission Yeast

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Directory of Open Access Journals

The Francis Crick Institute

Public Library of Science (PLOS)

Crossref