Coordinated regulation of mitochondrial topoisomerase IB with mitochondrial nuclear encoded genes and MYC

Mitochondrial DNA (mtDNA) is entirely dependent on nuclear genes for its transcription and replication. One of these genes is TOP1MT, which encodes the mitochondrial DNA topoisomerase IB, involved in mtDNA relaxation. To elucidate TOP1MT regulation, we performed genome-wide profiling across the 60-cell line panel (the NCI-60) of the National Cancer Institute Developmental Therapeutics Program. We show that TOP1MT mRNA expression varies widely across these cell lines with the highest levels in leukemia (HL-60, K-562) and melanoma (SK-MEL-28), intermediate levels in breast (MDA-MB-231), ovarian (OVCAR) and colon (HCT-116, HCT-15, KM-12), and lowest levels in renal (ACHN, A498), prostate (PC-3, DU-145) and central nervous system cell lines (SF-539, SF-268, SF-295). Genome-wide analyses show that TOP1MT expression is significantly correlated with the other mitochondrial nuclear-encoded genes including the mitochondrial nucleoid genes, and demonstrate an overall co-regulation of the mitochondrial nuclear-encoded genes. We also find very high correlation between the expression of TOP1MT and the proto-oncogene MYC (c-myc). TOP1MT contains E-boxes (c-myc binding sites) and TOP1MT transcription follows MYC up- and down-regulation by MYC promoter activation and siRNA against MYC. Our finding implicates MYC as a novel regulator of TOP1MT and confirms its role as a master regulator of MNEGs and mitochondrial nucleoids.

[1]  D. Botstein,et al.  A gene expression database for the molecular pharmacology of cancer , 2000, Nature Genetics.

[2]  H. Erdjument-Bromage,et al.  MTERF3 Is a Negative Regulator of Mammalian mtDNA Transcription , 2007, Cell.

[3]  James H Doroshow,et al.  Analysis of Food and Drug Administration–Approved Anticancer Agents in the NCI60 Panel of Human Tumor Cell Lines , 2010, Molecular Cancer Therapeutics.

[4]  T. Umata,et al.  Expression of the TAF4b gene is induced by MYC through a non-canonical, but not canonical, E-box which contributes to its specific response to MYC. , 2008, International journal of oncology.

[5]  Albert Sickmann,et al.  Multiple pathways for sorting mitochondrial precursor proteins , 2008, EMBO reports.

[6]  N. Larsson,et al.  Mitochondrial DNA mutations in disease and aging , 2011, The Journal of cell biology.

[7]  William C Reinhold,et al.  Integrating data on DNA copy number with gene expression levels and drug sensitivities in the NCI-60 cell line panel , 2006, Molecular Cancer Therapeutics.

[8]  D. Moore,et al.  The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  John D. Watson,et al.  Identifying Genes Regulated in a Myc-dependent Manner* , 2002, The Journal of Biological Chemistry.

[10]  A. Menssen,et al.  Characterization of the c-MYC-regulated transcriptome by SAGE: Identification and analysis of c-MYC target genes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Y. Pommier,et al.  Mitochondrial topoisomerases and alternative splicing of the human TOP1mt gene. , 2007, Biochimie.

[12]  D. Wallace.  A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine , 2005, Annual review of genetics.

[13]  Wenyi Wang,et al.  Identification of rare DNA variants in mitochondrial disorders with improved array-based sequencing , 2010, Nucleic Acids Res..

[14]  N. Neretti,et al.  The oncogene c-Myc coordinates regulation of metabolic networks to enable rapid cell cycle entry , 2008, Cell cycle.

[15]  R. Eisenman,et al.  The Myc/Max/Mad network and the transcriptional control of cell behavior. , 2000, Annual review of cell and developmental biology.

[16]  H. Woo,et al.  Integrative Analysis of Proteomic Signatures, Mutations, and Drug Responsiveness in the NCI 60 Cancer Cell Line Set , 2010, Molecular Cancer Therapeutics.

[17]  A. Reyes,et al.  Mammalian mitochondrial nucleoids: organizing an independently minded genome. , 2007, Mitochondrion.

[18]  W. Reinhold,et al.  Genome-Wide mRNA and microRNA Profiling of the NCI 60 Cell-Line Screen and Comparison of FdUMP[10] with Fluorouracil, Floxuridine, and Topoisomerase 1 Poisons , 2010, Molecular Cancer Therapeutics.

[19]  Zhiping Weng,et al.  Global mapping of c-Myc binding sites and target gene networks in human B cells , 2006, Proceedings of the National Academy of Sciences.

[20]  Yves Pommier,et al.  DNA topoisomerases and their poisoning by anticancer and antibacterial drugs. , 2010, Chemistry & biology.

[21]  William C Reinhold,et al.  Proteomic profiling of the NCI-60 cancer cell lines using new high-density reverse-phase lysate microarrays , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[22]  Kathryn A. O’Donnell,et al.  Myc Stimulates Nuclearly Encoded Mitochondrial Genes and Mitochondrial Biogenesis , 2005, Molecular and Cellular Biology.

[23]  Y. Pommier,et al.  Thirteen-exon-motif signature for vertebrate nuclear and mitochondrial type IB topoisomerases. , 2004, Nucleic acids research.

[24]  Jae K. Lee,et al.  Transcript and protein expression profiles of the NCI-60 cancer cell panel: an integromic microarray study , 2007, Molecular Cancer Therapeutics.

[25]  R. Shoemaker.  The NCI60 human tumour cell line anticancer drug screen , 2006, Nature Reviews Cancer.

[26]  L. Galluzzi,et al.  Targeting mitochondria for cancer therapy , 2010, Nature Reviews Drug Discovery.

[27]  R. Scarpulla,et al.  Nuclear control of respiratory gene expression in mammalian cells , 2006, Journal of cellular biochemistry.

[28]  S. Carr,et al.  A Mitochondrial Protein Compendium Elucidates Complex I Disease Biology , 2008, Cell.

[29]  J. N. Spelbrink.  Functional organization of mammalian mitochondrial DNA in nucleoids: History, recent developments, and future challenges , 2009, IUBMB life.

[30]  C. Dang,et al.  MYC-Induced Cancer Cell Energy Metabolism and Therapeutic Opportunities , 2009, Clinical Cancer Research.

[31]  R. Scarpulla.  Transcriptional paradigms in mammalian mitochondrial biogenesis and function. , 2008, Physiological reviews.

[32]  H. Erdjument-Bromage,et al.  MTERF2 is a nucleoid component in mammalian mitochondria. , 2009, Biochimica et biophysica acta.

[33]  J. Champoux.  DNA topoisomerases: structure, function, and mechanism. , 2001, Annual review of biochemistry.

[34]  Y. Pommier,et al.  Human mitochondrial topoisomerase I , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[35]  Morten O. Christensen,et al.  Adaptation of topoisomerase I paralogs to nuclear and mitochondrial DNA , 2009, Nucleic acids research.

[36]  D. Clayton.  Mitochondrial DNA Replication: What We Know , 2003, IUBMB life.

[37]  B. Edgar,et al.  Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. , 2003, Genes & development.

[38]  D. Wallace,et al.  Role of SUV3 Helicase in Maintaining Mitochondrial Homeostasis in Human Cells* , 2008, Journal of Biological Chemistry.

[39]  Jonghwan Kim,et al.  Global Identification of Myc Target Genes Reveals Its Direct Role in Mitochondrial Biogenesis and Its E-Box Usage In Vivo , 2008, PloS one.

[40]  H. Endo,et al.  Human prohibitin 1 maintains the organization and stability of the mitochondrial nucleoids. , 2008, Experimental cell research.

[41]  J. Weinstein,et al.  Karyotypic complexity of the NCI-60 drug-screening panel. , 2003, Cancer research.

[42]  E. Lander,et al.  Expression analysis with oligonucleotide microarrays reveals that MYC regulates genes involved in growth, cell cycle, signaling, and adhesion. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[43]  William C Reinhold,et al.  Exon array analyses across the NCI-60 reveal potential regulation of TOP1 by transcription pausing at guanosine quartets in the first intron. , 2010, Cancer research.

[44]  James C. Wang.  A journey in the world of DNA rings and beyond. , 2009, Annual review of biochemistry.

[45]  J. Weinstein,et al.  mRNA and microRNA Expression Profiles of the NCI-60 Integrated with Drug Activities , 2010, Molecular Cancer Therapeutics.

[46]  D. Bogenhagen,et al.  Human DNA2 is a mitochondrial nuclease/helicase for efficient processing of DNA replication and repair intermediates and defective in myopathy , 2008, Molecular cell.

[47]  S. Batalov,et al.  A gene atlas of the mouse and human protein-encoding transcriptomes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[48]  N. Lee,et al.  Identification of c-myc responsive genes using rat cDNA microarray. , 2000, Cancer research.

[49]  D. Rousseau,et al.  The Layered Structure of Human Mitochondrial DNA Nucleoids* , 2008, Journal of Biological Chemistry.

[50]  John M Sedivy,et al.  A Large Scale Genetic Analysis of c-Myc-regulated Gene Expression Patterns* 210 , 2003, The Journal of Biological Chemistry.

[51]  Y. Pommier,et al.  Mitochondrial topoisomerase I sites in the regulatory D-loop region of mitochondrial DNA. , 2008, Biochemistry.