Signature of Progression and Negative Outcome in Colorectal Cancer
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Functional Roles of Bromodomain Proteins in Cancer
cancers Review Functional Roles of Bromodomain Proteins in Cancer Samuel P. Boyson 1,2, Cong Gao 3, Kathleen Quinn 2,3, Joseph Boyd 3, Hana Paculova 3 , Seth Frietze 3,4,* and Karen C. Glass 1,2,4,* 1 Department of Pharmaceutical Sciences, Albany College of Pharmacy and Health Sciences, Colchester, VT 05446, USA; [email protected] 2 Department of Pharmacology, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA; [email protected] 3 Department of Biomedical and Health Sciences, University of Vermont, Burlington, VT 05405, USA; [email protected] (C.G.); [email protected] (J.B.); [email protected] (H.P.) 4 University of Vermont Cancer Center, Burlington, VT 05405, USA * Correspondence: [email protected] (S.F.); [email protected] (K.C.G.) Simple Summary: This review provides an in depth analysis of the role of bromodomain-containing proteins in cancer development. As readers of acetylated lysine on nucleosomal histones, bromod- omain proteins are poised to activate gene expression, and often promote cancer progression. We examined changes in gene expression patterns that are observed in bromodomain-containing proteins and associated with specific cancer types. We also mapped the protein–protein interaction network for the human bromodomain-containing proteins, discuss the cellular roles of these epigenetic regu- lators as part of nine different functional groups, and identify bromodomain-specific mechanisms in cancer development. Lastly, we summarize emerging strategies to target bromodomain proteins in cancer therapy, including those that may be essential for overcoming resistance. Overall, this review provides a timely discussion of the different mechanisms of bromodomain-containing pro- Citation: Boyson, S.P.; Gao, C.; teins in cancer, and an updated assessment of their utility as a therapeutic target for a variety of Quinn, K.; Boyd, J.; Paculova, H.; cancer subtypes. -
Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model
Downloaded from http://www.jimmunol.org/ by guest on September 25, 2021 T + is online at: average * The Journal of Immunology , 34 of which you can access for free at: 2016; 197:1477-1488; Prepublished online 1 July from submission to initial decision 4 weeks from acceptance to publication 2016; doi: 10.4049/jimmunol.1600589 http://www.jimmunol.org/content/197/4/1477 Molecular Profile of Tumor-Specific CD8 Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. Waugh, Sonia M. Leach, Brandon L. Moore, Tullia C. Bruno, Jonathan D. Buhrman and Jill E. Slansky J Immunol cites 95 articles Submit online. Every submission reviewed by practicing scientists ? is published twice each month by Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts http://jimmunol.org/subscription Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html http://www.jimmunol.org/content/suppl/2016/07/01/jimmunol.160058 9.DCSupplemental This article http://www.jimmunol.org/content/197/4/1477.full#ref-list-1 Information about subscribing to The JI No Triage! Fast Publication! Rapid Reviews! 30 days* Why • • • Material References Permissions Email Alerts Subscription Supplementary The Journal of Immunology The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2016 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. This information is current as of September 25, 2021. The Journal of Immunology Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model Katherine A. -
How Shelterin Protects Mammalian Telomeres 303 ANRV361-GE42-15 ARI 3 October 2008 10:10 (See 3' 5' TRF2 S Mplex
ANRV361-GE42-15 ARI 3 October 2008 10:10 ANNUAL How Shelterin Protects REVIEWS Further Click here for quick links to Annual Reviews content online, Mammalian Telomeres including: • Other articles in this volume 1 • Top cited articles Wilhelm Palm and Titia de Lange • Top downloaded articles • Our comprehensive search Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021; email: [email protected] 1Current address: Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany Annu. Rev. Genet. 2008. 42:301–34 Key Words First published online as a Review in Advance on ATM, ATR, cancer, NHEJ, HR August 4, 2008 by Rockefeller University on 10/13/09. For personal use only. The Annual Review of Genetics is online at Abstract genet.annualreviews.org The genomes of prokaryotes and eukaryotic organelles are usually cir- This article’s doi: cular as are most plasmids and viral genomes. In contrast, the nuclear Annu. Rev. Genet. 2008.42:301-334. Downloaded from arjournals.annualreviews.org 10.1146/annurev.genet.41.110306.130350 genomes of eukaryotes are organized on linear chromosomes, which Copyright c 2008 by Annual Reviews. require mechanisms to protect and replicate DNA ends. Eukaryotes All rights reserved navigate these problemswith the advent of telomeres, protective nucle- 0066-4197/08/1201-0301$20.00 oprotein complexes at the ends of linear chromosomes, and telomerase, the enzyme that maintains the DNA in these structures. Mammalian telomeres contain a specific protein complex, shelterin, that functions to protect chromosome ends from all aspects of the DNA damage re- sponse and regulates telomere maintenance by telomerase. -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency
Published OnlineFirst March 24, 2014; DOI: 10.1158/0008-5472.CAN-13-3229 Cancer Therapeutics, Targets, and Chemical Biology Research ATR Pathway Inhibition Is Synthetically Lethal in Cancer Cells with ERCC1 Deficiency Kareem N. Mohni, Gina M. Kavanaugh, and David Cortez Abstract The DNA damage response kinase ATR and its effector kinase CHEK1 are required for cancer cells to survive oncogene-induced replication stress. ATR inhibitors exhibit synthetic lethal interactions, with deficiencies in the DNA damage response enzymes ATM and XRCC1 and with overexpression of the cell cycle kinase cyclin E. Here, we report a systematic screen to identify synthetic lethal interactions with ATR pathway–targeted drugs, rationalized by their predicted therapeutic utility in the oncology clinic. We found that reduced function in the ATR pathway itself provided the strongest synthetic lethal interaction. In addition, we found that loss of the structure-specific endonuclease ERCC1-XPF (ERCC4) is synthetic lethal with ATR pathway inhibitors. ERCC1- deficient cells exhibited elevated levels of DNA damage, which was increased further by ATR inhibition. When treated with ATR or CHEK1 inhibitors, ERCC1-deficient cells were arrested in S-phase and failed to complete cell-cycle transit even after drug removal. Notably, triple-negative breast cancer cells and non–small cell lung cancer cells depleted of ERCC1 exhibited increased sensitivity to ATR pathway–targeted drugs. Overall, we concluded that ATR pathway–targeted drugs may offer particular utility in cancers with reduced ATR pathway function or reduced levels of ERCC4 activity. Cancer Res; 74(10); 1–11. Ó2014 AACR. Introduction repair pathway such as homologous recombination or post- – Replicating DNA is sensitive to a wide array of endogenous replicative repair to remove the PARP DNA complexes (7). -
1 AGING Supplementary Table 2
SUPPLEMENTARY TABLES Supplementary Table 1. Details of the eight domain chains of KIAA0101. Serial IDENTITY MAX IN COMP- INTERFACE ID POSITION RESOLUTION EXPERIMENT TYPE number START STOP SCORE IDENTITY LEX WITH CAVITY A 4D2G_D 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ B 4D2G_E 52 - 69 52 69 100 100 2.65 Å PCNA X-RAY DIFFRACTION √ C 6EHT_D 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ D 6EHT_E 52 - 71 52 71 100 100 3.2Å PCNA X-RAY DIFFRACTION √ E 6GWS_D 41-72 41 72 100 100 3.2Å PCNA X-RAY DIFFRACTION √ F 6GWS_E 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ G 6GWS_F 41-72 41 72 100 100 2.9Å PCNA X-RAY DIFFRACTION √ H 6IIW_B 2-11 2 11 100 100 1.699Å UHRF1 X-RAY DIFFRACTION √ www.aging-us.com 1 AGING Supplementary Table 2. Significantly enriched gene ontology (GO) annotations (cellular components) of KIAA0101 in lung adenocarcinoma (LinkedOmics). Leading Description FDR Leading Edge Gene EdgeNum RAD51, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, CENPW, HJURP, NDC80, CDCA5, NCAPH, BUB1, ZWILCH, CENPK, KIF2C, AURKA, CENPN, TOP2A, CENPM, PLK1, ERCC6L, CDT1, CHEK1, SPAG5, CENPH, condensed 66 0 SPC24, NUP37, BLM, CENPE, BUB3, CDK2, FANCD2, CENPO, CENPF, BRCA1, DSN1, chromosome MKI67, NCAPG2, H2AFX, HMGB2, SUV39H1, CBX3, TUBG1, KNTC1, PPP1CC, SMC2, BANF1, NCAPD2, SKA2, NUP107, BRCA2, NUP85, ITGB3BP, SYCE2, TOPBP1, DMC1, SMC4, INCENP. RAD51, OIP5, CDK1, SPC25, CCNB1, BIRC5, NCAPG, ZWINT, MAD2L1, SKA3, NUF2, BUB1B, CENPA, SKA1, AURKB, NEK2, ESCO2, CENPW, HJURP, TTK, NDC80, CDCA5, BUB1, ZWILCH, CENPK, KIF2C, AURKA, DSCC1, CENPN, CDCA8, CENPM, PLK1, MCM6, ERCC6L, CDT1, HELLS, CHEK1, SPAG5, CENPH, PCNA, SPC24, CENPI, NUP37, FEN1, chromosomal 94 0 CENPL, BLM, KIF18A, CENPE, MCM4, BUB3, SUV39H2, MCM2, CDK2, PIF1, DNA2, region CENPO, CENPF, CHEK2, DSN1, H2AFX, MCM7, SUV39H1, MTBP, CBX3, RECQL4, KNTC1, PPP1CC, CENPP, CENPQ, PTGES3, NCAPD2, DYNLL1, SKA2, HAT1, NUP107, MCM5, MCM3, MSH2, BRCA2, NUP85, SSB, ITGB3BP, DMC1, INCENP, THOC3, XPO1, APEX1, XRCC5, KIF22, DCLRE1A, SEH1L, XRCC3, NSMCE2, RAD21. -
Supplementary Table S1. Correlation Between the Mutant P53-Interacting Partners and PTTG3P, PTTG1 and PTTG2, Based on Data from Starbase V3.0 Database
Supplementary Table S1. Correlation between the mutant p53-interacting partners and PTTG3P, PTTG1 and PTTG2, based on data from StarBase v3.0 database. PTTG3P PTTG1 PTTG2 Gene ID Coefficient-R p-value Coefficient-R p-value Coefficient-R p-value NF-YA ENSG00000001167 −0.077 8.59e-2 −0.210 2.09e-6 −0.122 6.23e-3 NF-YB ENSG00000120837 0.176 7.12e-5 0.227 2.82e-7 0.094 3.59e-2 NF-YC ENSG00000066136 0.124 5.45e-3 0.124 5.40e-3 0.051 2.51e-1 Sp1 ENSG00000185591 −0.014 7.50e-1 −0.201 5.82e-6 −0.072 1.07e-1 Ets-1 ENSG00000134954 −0.096 3.14e-2 −0.257 4.83e-9 0.034 4.46e-1 VDR ENSG00000111424 −0.091 4.10e-2 −0.216 1.03e-6 0.014 7.48e-1 SREBP-2 ENSG00000198911 −0.064 1.53e-1 −0.147 9.27e-4 −0.073 1.01e-1 TopBP1 ENSG00000163781 0.067 1.36e-1 0.051 2.57e-1 −0.020 6.57e-1 Pin1 ENSG00000127445 0.250 1.40e-8 0.571 9.56e-45 0.187 2.52e-5 MRE11 ENSG00000020922 0.063 1.56e-1 −0.007 8.81e-1 −0.024 5.93e-1 PML ENSG00000140464 0.072 1.05e-1 0.217 9.36e-7 0.166 1.85e-4 p63 ENSG00000073282 −0.120 7.04e-3 −0.283 1.08e-10 −0.198 7.71e-6 p73 ENSG00000078900 0.104 2.03e-2 0.258 4.67e-9 0.097 3.02e-2 Supplementary Table S2. -
Tgfb1 Cell Cycle Arrest Is Mediated by Inhibition of MCM Assembly in Rb-Deficient Conditions Brook S
Published OnlineFirst September 26, 2018; DOI: 10.1158/1541-7786.MCR-18-0558 Signal Transduction Molecular Cancer Research TGFb1 Cell Cycle Arrest Is Mediated by Inhibition of MCM Assembly in Rb-deficient Conditions Brook S. Nepon-Sixt and Mark G. Alexandrow Abstract Transforming growth factor b1 (TGFb1) is a potent inhib- expression prevents TGFb1 suppression of MCM assembly. itor of cell growth that targets gene-regulatory events, but Mechanistically, TGFb1 blocks a Cyclin E–Mcm7 molecular also inhibits the function of CDC45-MCM-GINS helicases interaction required for MCM hexamer assembly upstream of (CMG; MCM, Mini-Chromosome Maintenance; GINS, Go- CDC10-dependent transcript-1 (CDT1) function. Accordingly, Ichi-Ni-San) through multiple mechanisms to achieve cell- overexpression of CDT1 with an intact MCM-binding domain cycle arrest. Early in G1, TGFb1 blocks MCM subunit expres- abrogates TGFb1 arrest and rescues MCM assembly. The ability sion and suppresses Myc and Cyclin E/Cdk2 activity required of CDT1 to restore MCM assembly and allow S-phase entry for CMG assembly, should MCMs be expressed. Once CMGs indicates that, in the absence of Rb and other canonical med- are assembled in late-G1, TGFb1 blocks CMG activation using iators, TGFb1 relies on inhibition of Cyclin E-MCM7 and MCM a direct mechanism involving the retinoblastoma (Rb) tumor assembly to achieve cell cycle arrest. suppressor. Here, in cells lacking Rb, TGFb1 does not suppress Myc, Cyclin E/Cdk2 activity, or MCM expression, yet growth Implication: These results demonstrate that the MCM assem- arrest remains intact and Smad2/3/4-dependent. Such arrest bly process is a pivotal target of TGFb1 in eliciting cell cycle occurs due to inhibition of MCM hexamer assembly by TGFb1, arrest, and provide evidence for a novel oncogenic role for which is not seen when Rb is present and MCM subunit CDT1 in abrogating TGFb1 inhibition of MCM assembly. -
Gene Expression Profiling Analysis Contributes to Understanding the Association Between Non-Syndromic Cleft Lip and Palate, and Cancer
2110 MOLECULAR MEDICINE REPORTS 13: 2110-2116, 2016 Gene expression profiling analysis contributes to understanding the association between non-syndromic cleft lip and palate, and cancer HONGYI WANG, TAO QIU, JIE SHI, JIULONG LIANG, YANG WANG, LIANGLIANG QUAN, YU ZHANG, QIAN ZHANG and KAI TAO Department of Plastic Surgery, General Hospital of Shenyang Military Area Command, PLA, Shenyang, Liaoning 110016, P.R. China Received March 10, 2015; Accepted December 18, 2015 DOI: 10.3892/mmr.2016.4802 Abstract. The present study aimed to investigate the for NSCL/P were implicated predominantly in the TGF-β molecular mechanisms underlying non-syndromic cleft lip, signaling pathway, the cell cycle and in viral carcinogenesis. with or without cleft palate (NSCL/P), and the association The TP53, CDK1, SMAD3, PIK3R1 and CASP3 genes were between this disease and cancer. The GSE42589 data set found to be associated, not only with NSCL/P, but also with was downloaded from the Gene Expression Omnibus data- cancer. These results may contribute to a better understanding base, and contained seven dental pulp stem cell samples of the molecular mechanisms of NSCL/P. from children with NSCL/P in the exfoliation period, and six controls. Differentially expressed genes (DEGs) were Introduction screened using the RankProd method, and their potential functions were revealed by pathway enrichment analysis and Non-syndromic cleft lip, with or without cleft palate (NSCL/P) construction of a pathway interaction network. Subsequently, is one of the most common types of congenital defect and cancer genes were obtained from six cancer databases, and affects 3.4-22.9/10,000 individuals worldwide (1). -
MCM7 Antibody (R30890)
MCM7 Antibody (R30890) Catalog No. Formulation Size R30890 0.5mg/ml if reconstituted with 0.2ml sterile DI water 100 ug Bulk quote request Availability 1-3 business days Species Reactivity Human Format Antigen affinity purified Clonality Polyclonal (rabbit origin) Isotype Rabbit IgG Purity Antigen affinity Buffer Lyophilized from 1X PBS with 2.5% BSA and 0.025% sodium azide/thimerosal UniProt P33993 Applications Western blot : 0.5-1ug/ml IHC (FFPE) : 0.5-1ug/ml Immunocytochemistry : 0.5-1ug/ml Flow cytometry : 1-3ug/million cells Limitations This MCM7 antibody is available for research use only. Western blot testing of MCM7 antibody and Lane 1: COLO320; 2: SW620; 3: HeLa; 4: 22RVL; 5: 293T; 6: U937; 7: Jurkat; 8: Raji cell lysate. Expected size 80~90KD IHC-P: MCM7 antibody testing of human lung cancer tissue ICC testing of MCM7 antibody and MCF-7 cells ICC testing of MCM7 antibody and HeLa cells Flow cytometry testing of human A431 cells with MCM7 antibody at 1ug/million cells (blocked with goat sera); Red=cells alone, Green=isotype control, Blue= MCM7 antibody. Description Minichromosome Maintenance, s. Cerevisiae, homolog of, 7, also called CDC47, is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. MCM7 plays a pivotal role in the G1/S phase transition, orchestrating the correct assembly of replication forks on chromosomal DNA and ensuring that all the genome is replicated once and not more than once at each cell cycle. The gene contains 15 exons. The miRNAs MIR106B, MIR93, and MIR25 are clustered in a 5-prime to 3-prime orientation within intron 13. -
Cell Cycle-Dependent Modification of Pot1 and Its Effects on Telomere
Cell cycle-dependent modification of Pot1 and its effects on telomere function Vitaliy Kuznetsov Thesis submitted towards the degree of Doctor of Philosophy University College of London Department of Biology London, WC1E 6BT The program of research was carried out at Cancer Research U.K. Laboratory of Telomere Biology 44 Lincoln’s Inn Fields, London, U.K. WC2A 3PX Supervisor: Dr Julia Promisel Cooper September 2008 I, Vitaliy Kuznetsov, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. ABSTRACT Telomere functions are tightly controlled throughout the cell cycle to allow telomerase access while suppressing a bona fide DNA damage response (DDR) at linear chromosome ends. However, the mechanisms that link cell cycle progression with telomere functions are largely unknown. Here we show that a key S-phase kinase, DDK (Dbf4-dependent protein kinase), phosphorylates the telomere binding protein Pot1, and that this phosphorylation is crucial for DNA damage checkpoint inactivation, the suppression of homologous recombination (HR) at telomeres, and the prevention of telomere loss. DDK phosphorylates Pot1 in a very conserved region of its most amino-terminal-proximal OB fold, suggesting that this regulation of telomere function may be widely conserved. Mutation of Pot1 phosphorylation sites leads to telomerase independent telomere maintenance through constant HR, as well as a dependence of telomere maintenance proteins involved in checkpoint activation and HR. These results uncover a novel and important link between DDR suppression and telomere maintenance. The failure in Pot1 phosphorylation and DDR inactivation could potentially lead to uncontrolled cell proliferation without a requirement for telomerase by switching cells to HR dependent telomere homeostasis. -
Human Origin Recognition Complex Is Essential for HP1 Binding to Chromatin and Heterochromatin Organization
Human origin recognition complex is essential for HP1 binding to chromatin and heterochromatin organization Supriya G. Prasantha,b,1, Zhen Shenb, Kannanganattu V. Prasanthb, and Bruce Stillmana,1 aCold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724; and bDepartment of Cell and Developmental Biology, University of Illinois, Urbana- Champaign, IL 61801 Contributed by Bruce Stillman, July 9, 2010 (sent for review April 10, 2010) The origin recognition complex (ORC) is a DNA replication initiator (15, 22, 23), cytokinesis in human cells and Drosophila (24, 25), protein also known to be involved in diverse cellular functions regulation of dendrite development in postmitotic neurons (26), including gene silencing, sister chromatid cohesion, telomere bi- and neural transmission and synaptic function in Drosophila (27) ology, heterochromatin localization, centromere and centrosome (see reviews in refs. 28, 29). activity, and cytokinesis. We show that, in human cells, multiple ORC The human Orc2 subunit is associated with heterochromatin in subunits associate with hetereochromatin protein 1 (HP1) α-and a cell cycle-dependent manner, being present only at the cen- HP1β-containing heterochromatic foci. Fluorescent bleaching studies tromeres during late G2 and mitosis (15, 30). Furthermore, Orc2 indicate that multiple subcomplexes of ORC exist at heterochroma- biochemically interacts indirectly with the heterochromatin protein tin, with Orc1 stably associating with heterochromatin in G1 phase, 1 (HP1) in mammalian, Drosophila,andXenopus cells (14, 15, 31, whereas other ORC subunits have transient interactions throughout 32). Depletion of Orc2 or Orc3 in HeLa cells results in a mitotic the cell-division cycle. Both Orc1 and Orc3 directly bind to HP1α,and arrest with abnormally condensed chromosomes, lack of chromo- two domains of Orc3, a coiled-coil domain and a mod-interacting some alignment at the metaphase plate, and spindle defects (15).