Fall 2015

Jared Rutter Receives Esteemed HHMI Grant

NC Program Members

Melinda Angus-Hill, PhD

Donald Ayer, PhD

Brenda Bass, PhD

Srividya Bhaskara, PhD

Andrea Bild, PhD

Cynthia Burrows, PhD

Bradley Cairns, PhD

Mario Capecchi, PhD

Dana Carroll, PhD

Demián Cazalla, PhD

Mahesh Chandrasekharan, PhD

Michael Engel, MD, PhD

Timothy Formosa, PhD

Jason Gertz, PhD

Kent Golic, PhD

Barbara Graves, PhD

David Grunwald, PhD

Christopher Hill, PhD

L. Eric Huang, MD, PhD

Kevin Jones, MD

Elizabeth Leibold, PhD

Rodney Miles, MD, PhD

Ryan O’Connell, PhD

Josef Prchal, MD

Jared Rutter, PhD

Joshua Schiffman, MD

Eric Snyder, MD, PhD

Sankar Swaminathan, MD

Dean Tantin, PhD

Carl Thummel, PhD

Katherine Varley, PhD

Li Wang, PhD

Dennis Winge, PhD

In May 2015, Nuclear Control Program member and co-leader Jared Rutter, PhD, received the highly prestigious honor of being selected as 1 of the 26 scientists to be appointed as a new investigator with the Howard Hughes Medical Institute (HHMI). His research focuses on the crucial roles of mitochondria in metabolism and cell biology. Rutter’s work has impacted our understanding of human metabolism and its connection to

potentially fatal illnesses, including cancer. His collaborative work with Carl Thummel, PhD, Professor with the Department of Human Genetics and also a Nuclear Control program member, has identified the Mpc1 and Mpc2 proteins, which together determine the metabolic fate of carbohydrates, by enabling mitochondrial import of pyruvate. They continue to define the role of the Mpc1/Mpc2 complex, particularly in the the metabolic defects in cancer and heart disease, and the roles Mpc1 and Mpc2 play in impairing tumorigenic potential of cancer cells. With his five-year HHMI award, Rutter will continue researching metabolism and its relationship to cancer and diabetes, among other illnesses. Rutter is a Professor of Biochemistry and the Dee Glen and Ida Smith Endowed Chair for Cancer Research at the University of Utah.

Jared Rutter

2015 Awards Renewed HHMI Grant

Jay Gertz and Nicki Camp Awarded Pilot Project

Brad Cairns has been awarded a renewal of his HHMI grant, which will mark his fourth HHMI award cycle. With this renewal, Brad will continue to research regulation of chromatin remodeling; chromatin of germ cells and early development in zebrafish and humans; and DNA and RNA methylation dynamics.

Jay Gertz and Nicki Camp were awarded a pilot project that was jointly funded by the Nuclear Control of Cell Growth and Differentiation program and the Cancer Control and Population Sciences program. The goal of the project is to functionally fine map non-coding SNPs within a haplotype associated with increased breast cancer risk.

Selected 2015 Publications

Alexander M, Hu R, Runtsch MC, Kagele DA, Mosbruger TL, Tolmachova T, Seabra MC, Round JL, Ward DM, O'Connell RM (2015) Exosome-delivered microRNAs modulate the inflammatory response to endotoxin. Nat Commun. 6:7321.

Alshykhly OR, Fleming AM, Burrows CJ (2015) 5-Carboxamido-5-formamido-2-iminohydantoin, in Addition to 8-oxo-7,8-Dihydroguanine, is the major product of the Iron-Fenton or X-ray radiation-induced oxidation of guanine under aerobic reducing conditions in nucleoside and DNA Contexts. J Org Chem. 80:6996-7007.

An N, Fleming AM, White HS, Burrows CJ (2015) Nanopore detection of 8-oxoguanine in the human telomere repeat sequence. ACS Nano. 9:4296-307.

Bhaskara S (2015) Histone deacetylases 1 and 2 regulate DNA replication and DNA repair: Potential targets for genome stability-mechanism-based therapeutics for a subset of cancers. Cell Cycle. 14:1779-85.

Carroll D (2015) Genome editing by targeted chromosomal mutagenesis. Methods Mol Biol. 1239:1-13.

Choi H, Gillespie DL, Berg S, Rice C, Couldwell S, Gu J, Colman H, Jensen RL, Huang LE (2015) Intermittent induction of HIF-1α produces lasting effects on malignant progression independent of its continued expression. PLoS ONE. 10:e0125125.

Christensen RD, Lambert DK, Henry E, Yaish HM, Prchal JT (2015) End-tidal carbon monoxide as an indicator of the hemolytic rate. Blood Cells Mol Dis. 54:292-6.

Cohen A, Sato M, Aldape K, Mason CC, Alfaro-Munoz K, Heathcock L, South ST, Abegglen LM, Schiffman JD, Colman H (2015) DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status. Acta Neuropathol Commun. 3:34.

Fadul J, Bell R, Hoffman LM, Beckerle MC, Engel ME, Lessnick SL (2015) EWS/FLI utilizes NKX2-2 to repress mesenchymal features of Ewing sarcoma. Genes Cancer. 6:129-43.

Fleming AM, Armentrout EI, Zhu J, Muller JG, Burrows CJ (2015) Spirodi(iminohydantoin) products from oxidation of 2'-deoxyguanosine in the presence of NH4Cl in nucleoside and oligodeoxynucleotide contexts. J Org Chem. 80:711-21.

Thursday Laboratory Event Held: Thursdays, HCI 3 South, 12 Noon PIs can give and receive feedback from HCI colleagues about upcoming grant submissions. Nuclear Control and Cell Response and Regulation members are invited to attend. To schedule your grant review, contact Jessica Chapman at 5-2887 or Jessica.chapman@hci.utah.edu.

New NC Program Members Eric Snyder, MD, PhD Eric Snyder joined Huntsman Cancer Institute as an Investigator and the Department of Pathology (University of Utah) as an Assistant Professor in August 2015. His lab’s research works to determine how the loss of cellular identity and acquisition of alternative differentiation states contributes to cancer progression and alters therapeutic response.

Demián Cazalla, PhD

Demián Cazalla is an Investigator with Huntsman Cancer Institute and an Assistant Professor with the Department of Biochemistry (University of Utah). His lab focuses on regulation of gene expression and functions of viral and cellular non-coding RNAs.

2015 Winter Symposium: Cancer Metabolism Held: December 14, 2015, 3:00pm – 7:30pm

Jewish Community Center The symposium will be used as a platform for NC Investigators to listen to one another’s expertise and experiences in order to brainstorm the next actions and direction Investigators should take their NC program research in cancer metabolism. Dinner will be provided.

Hammond E, Lang J, Maeda Y, Pleasure D, Angus-Hill M, Xu J, Horiuchi M, Deng W, Guo F (2015) The Wnt effector transcription factor 7-like 2 positively regulates oligodendrocyte differentiation in a manner independent of Wnt/β-catenin signaling. J Neurosci. 35:5007-22.

Han H, Monroe N, Votteler J, Shakya B, Sundquist WI, Hill CP (2015) Binding of substrates to the central pore of the Vps4 ATPase is autoinhibited by the microtubule interacting and trafficking (MIT) domain and activated by MIT interacting motifs (MIMs). J Biol Chem. 290:13490-9.

Johnson DP, Spitz GS, Tharkar S, Quayle SN, Shearstone JR, Jones S, McDowell ME, Wellman H, Tyler JK, Cairns BR, Chandrasekharan MB, Bhaskara S (2015) HDAC1,2 inhibition impairs EZH2- and BBAP-mediated DNA repair to overcome chemoresistance in EZH2 gain-of-function mutant diffuse large B-cell lymphoma. Oncotarget. 6:4863-87.

Jones KB (2015) Transposon mutagenesis disentangles osteosarcoma genetic drivers. Nat Genet. 47:564-5.

Kaadige MR, Yang J, Wilde BR, Ayer DE (2015) MondoA-Mlx transcriptional activity is limited by mTOR-MondoA interaction. Mol Cell Biol. 35:101-10.

Nunney L, Maley CC, Breen M, Hochberg ME, Schiffman JD (2015) Peto's paradox and the promise of comparative oncology. Philos Trans R Soc Lond., B, Biol Sci 370:20140177.

Parang B, Rosenblatt D, Williams AD, Washington MK, Revetta F, Short SP, Reddy VK, Hunt A, Shroyer NF, Engel ME, Hiebert SW, Williams CS (2015) The transcriptional corepressor MTGR1 regulates intestinal secretory lineage allocation. FASEB. J 29:786-95.

Parnell TJ, Schlichter A, Wilson BG, Cairns BR (2015) The chromatin remodelers RSC and ISW1 display functional and chromatin-based promoter antagonism. Elife. 4:e06073.

Perera RT, Fleming AM, Johnson RP, Burrows CJ, White HS (2015) Detection of benzo[a]pyrene-guanine adducts in single-stranded DNA using the α-hemolysin nanopore. Nanotechnology. 26:074002.

Pomicter AD, Eiring AM, Senina AV, Zabriskie MS, Marvin JE, Prchal JT, O'Hare T, Deininger MW (2015) Limited efficacy of BMS-911543 in a murine model of Janus kinase 2 V617F myeloproliferative neoplasm. Exp Hematol. 43:537-545.e11.

Rutter J, Hughes AL (2015) Power(2): The power of yeast genetics applied to the powerhouse of the cell. Trends Endocrinol Metab 26:59-68.

Shakya A, Callister C, Goren A, Yosef N, Garg N, Khoddami V, Nix D, Regev A, Tantin D (2015) Pluripotency transcription factor Oct4 mediates stepwise nucleosome demethylation and depletion. Mol Cell Biol. 35:1014-25.

Shen L, O'Shea JM, Kaadige MR, Cunha S, Wilde BR, Cohen AL, Welm AL, Ayer DE (2015) Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP. Proc Natl Acad Sci U.S.A. 112:5425-30.

Shen Y, Rahman M, Piccolo SR, Gusenleitner D, El-Chaar NN, Cheng L, Monti S, Bild AH, Johnson WE (2015) ASSIGN: Context-specific genomic profiling of multiple heterogeneous biological pathways. Bioinformatics. 31:1745-53.

Sinha NK, Trettin KD, Aruscavage PJ, Bass BL (2015) Drosophila dicer-2 cleavage is mediated by helicase- and dsRNA termini-dependent states that are modulated by Loquacious-PD. Mol Cell. 58:406-17.

Song J, Yoon D, Christensen RD, Horvathova M, Thiagarajan P, Prchal JT (2015) HIF-mediated increased ROS from reduced mitophagy and decreased catalase causes neocytolysis. J Mol Med. 93:857-66.

Verma D, Li DJ, Krueger B, Renne R, Swaminathan S (2015) Identification of the physiological gene targets of the essential lytic replicative Kaposi's sarcoma-associated herpesvirus ORF57 protein. J Virol. 89:1688-702.

Whipple JM, Youssef OA, Aruscavage PJ, Nix DA, Hong C, Johnson WE, Bass BL (2015) Genome-wide profiling of the C. elegans dsRNAome. RNA. 21:786-800.

Youssef OA, Safran SA, Nakamura T, Nix DA, Hotamisligil GS, Bass BL (2015) Potential role for snoRNAs in PKR activation during metabolic stress. Proc Natl Acad Sci U.S.A. 112:5023-8.

Zhou J, Fleming AM, Averill AM, Burrows CJ, Wallace SS (2015) The NEIL glycosylases remove oxidized guanine lesions from telomeric and promoter quadruplex DNA structures. Nucleic Acids Res. 43:4039-54.

de Andrea CE, Zhu JF, Jin H, Bovée JV, Jones KB (2015) Cell cycle deregulation and mosaic loss of Ext1 drive peripheral chondrosarcomagenesis in the mouse and reveal an intrinsic cilia deficiency. J Pathol. 236:210-8.