Home LiteratureArticle Details
PMID: 10891483 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

In vitro properties of the conserved mammalian protein hnRNP D suggest a role in telomere maintenance.

Molecular and cellular biology ·Vol. 20 ·No. 15 ·2000-08-00 ·Pages 5425-32

Eversole A, Maizels N

Abstract

Mammalian chromosomes terminate with a 3' tail which consists of reiterations of the G-rich repeat, d(TTAGGG). The telomeric tail is the primer for replication by telomerase, and it may also invade telomeric duplex DNA to form terminal lariat structures, or T loops. Here we show that the ubiquitous and highly conserved mammalian protein hnRNP D interacts specifically with the G-rich strand of the telomeric repeat. A single gene encodes multiple isoforms of hnRNP D. All isoforms bind comparably to the G-rich strand, and certain isoforms can also bind tightly and specifically to the C-rich telomeric strand. G-rich telomeric sequences readily form structures stabilized by G-G pairing, which can interfere with telomere replication by telomerase. We show that hnRNP D binding to the G-rich strand destabilizes intrastrand G-G pairing and that hnRNP D interacts specifically with telomerase in human cell extracts. This biochemical analysis suggest that hnRNP D could function in vivo to destabilize structures formed by telomeric G-rich tails and facilitate their extension by telomerase.

MeSH Terms
Amino Acid Sequence Animals Conserved Sequence Heterogeneous-Nuclear Ribonucleoproteins Humans Mammals Molecular Sequence Data Protein Isoforms/metabolism RNA, Heterogeneous Nuclear/metabolism Repetitive Sequences, Nucleic Acid Ribonucleoproteins/metabolism Substrate Specificity Telomerase/metabolism Telomere/genetics,metabolism
Chemicals
Heterogeneous-Nuclear Ribonucleoproteins Protein Isoforms RNA, Heterogeneous Nuclear Ribonucleoproteins Telomerase
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Eversole A
Departments of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8024, USA.
Maizels N
References (66)
66 references, click to expand
  1. RAP1: a protean regulator in yeast.
    Trends Genet. 1994 Nov;10(11):408-12 PMID: 7809947
  2. An in vitro assay for Saccharomyces telomerase requires EST1.
    Cell. 1995 Jun 30;81(7):1127-35 PMID: 7600580
  3. Est1 and Cdc13 as comediators of telomerase access.
    Science. 1999 Oct 1;286(5437):117-20 PMID: 10506558
  4. Assembly and regulation of telomerase.
    Curr Opin Chem Biol. 1999 Oct;3(5):573-7 PMID: 10508671
  5. The Est1 subunit of yeast telomerase binds the Tlc1 telomerase RNA.
    Mol Cell Biol. 2000 Mar;20(6):1947-55 PMID: 10688642
  6. Identification of two human nuclear proteins that recognise the cytosine-rich strand of human telomeres in vitro.
    Nucleic Acids Res. 2000 Apr 1;28(7):1564-75 PMID: 10710423
  7. HuR binding to cytoplasmic mRNA is perturbed by heat shock.
    Proc Natl Acad Sci U S A. 2000 Mar 28;97(7):3073-8 PMID: 10737787
  8. Immunopurification of heterogeneous nuclear ribonucleoprotein particles reveals an assortment of RNA-binding proteins.
    Genes Dev. 1988 Feb;2(2):215-27 PMID: 3129338
  9. Formation of parallel four-stranded complexes by guanine-rich motifs in DNA and its implications for meiosis.
    Nature. 1988 Jul 28;334(6180):364-6 PMID: 3393228
  10. RNA binding specificity of hnRNP proteins: a subset bind to the 3' end of introns.
    EMBO J. 1988 Nov;7(11):3519-29 PMID: 3208740
  11. A mutant with a defect in telomere elongation leads to senescence in yeast.
    Cell. 1989 May 19;57(4):633-43 PMID: 2655926
  12. Monovalent cation-induced structure of telomeric DNA: the G-quartet model.
    Cell. 1989 Dec 1;59(5):871-80 PMID: 2590943
  13. Telomeric DNA dimerizes by formation of guanine tetrads between hairpin loops.
    Nature. 1989 Dec 14;342(6251):825-9 PMID: 2601741
  14. Inhibition of telomerase by G-quartet DNA structures.
    Nature. 1991 Apr 25;350(6320):718-20 PMID: 2023635
  15. Telomere loss: mitotic clock or genetic time bomb?
    Mutat Res. 1991 Mar-Nov;256(2-6):271-82 PMID: 1722017
  16. Novel DNA superstructures formed by telomere-like oligomers.
    Biochemistry. 1992 Jan 14;31(1):65-70 PMID: 1731885
  17. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2.
    Cell. 1992 Jan 24;68(2):365-75 PMID: 1531115
  18. Shuttling of pre-mRNA binding proteins between nucleus and cytoplasm.
    Nature. 1992 Feb 20;355(6362):730-2 PMID: 1371331
  19. A mammalian factor that binds telomeric TTAGGG repeats in vitro.
    Mol Cell Biol. 1992 Nov;12(11):4834-43 PMID: 1406665
  20. Hel-N1: an autoimmune RNA-binding protein with specificity for 3' uridylate-rich untranslated regions of growth factor mRNAs.
    Mol Cell Biol. 1993 Jun;13(6):3494-504 PMID: 8497264
  21. Nuclear proteins that bind the pre-mRNA 3' splice site sequence r(UUAG/G) and the human telomeric DNA sequence d(TTAGGG)n.
    Mol Cell Biol. 1993 Jul;13(7):4301-10 PMID: 8321232
  22. hnRNP proteins and the biogenesis of mRNA.
    Annu Rev Biochem. 1993;62:289-321 PMID: 8352591
  23. Purification, characterization, and cDNA cloning of an AU-rich element RNA-binding protein, AUF1.
    Mol Cell Biol. 1993 Dec;13(12):7652-65 PMID: 8246982
  24. The C-protein tetramer binds 230 to 240 nucleotides of pre-mRNA and nucleates the assembly of 40S heterogeneous nuclear ribonucleoprotein particles.
    Mol Cell Biol. 1994 Jan;14(1):518-33 PMID: 8264621
  25. Analysis of the RNA-recognition motif and RS and RGG domains: conservation in metazoan pre-mRNA splicing factors.
    Nucleic Acids Res. 1993 Dec 25;21(25):5803-16 PMID: 8290338
  26. The UUAG-specific RNA binding protein, heterogeneous nuclear ribonucleoprotein D0. Common modular structure and binding properties of the 2xRBD-Gly family.
    J Biol Chem. 1995 Sep 22;270(38):22167-75 PMID: 7673195
  27. Single-stranded DNA arising at telomeres in cdc13 mutants may constitute a specific signal for the RAD9 checkpoint.
    Mol Cell Biol. 1995 Nov;15(11):6128-38 PMID: 7565765
  28. A human telomeric protein.
    Science. 1995 Dec 8;270(5242):1663-7 PMID: 7502076
  29. Association of the Est1 protein with telomerase activity in yeast.
    Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2817-21 PMID: 8610124
  30. Cdc13p: a single-strand telomeric DNA-binding protein with a dual role in yeast telomere maintenance.
    Science. 1996 Oct 11;274(5285):249-52 PMID: 8824190
  31. The roles of heterogeneous nuclear ribonucleoproteins (hnRNP) in RNA metabolism.
    Bioessays. 1996 Sep;18(9):747-56 PMID: 8831291
  32. Evidence for a HeLa nuclear protein that binds specifically to the single-stranded d(CCCTAA)n telomeric motif.
    Nucleic Acids Res. 1996 Oct 15;24(20):4029-33 PMID: 8918808
  33. Structure, subnuclear distribution, and nuclear matrix association of the mammalian telomeric complex.
    J Cell Biol. 1996 Nov;135(4):867-81 PMID: 8922373
  34. The Saccharomyces CDC13 protein is a single-strand TG1-3 telomeric DNA-binding protein in vitro that affects telomere behavior in vivo.
    Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):13760-5 PMID: 8943008
  35. Est1 has the properties of a single-stranded telomere end-binding protein.
    Genes Dev. 1996 Dec 15;10(24):3094-104 PMID: 8985179
  36. TRF1, a mammalian telomeric protein.
    Trends Genet. 1997 Jan;13(1):21-6 PMID: 9009844
  37. A protein-counting mechanism for telomere length regulation in yeast.
    Science. 1997 Feb 14;275(5302):986-90 PMID: 9020083
  38. Recognition of telomeric DNA.
    Trends Biochem Sci. 1997 Feb;22(2):43-7 PMID: 9048479
  39. Long G tails at both ends of human chromosomes suggest a C strand degradation mechanism for telomere shortening.
    Cell. 1997 Mar 7;88(5):657-66 PMID: 9054505
  40. TRF1 is a dimer and bends telomeric DNA.
    EMBO J. 1997 Apr 1;16(7):1785-94 PMID: 9130722
  41. Identification of HuR as a protein implicated in AUUUA-mediated mRNA decay.
    EMBO J. 1997 Apr 15;16(8):2130-9 PMID: 9155038
  42. Telomeres, not the end of the story.
    Bioessays. 1997 May;19(5):367-70 PMID: 9174401
  43. The terminal DNA structure of mammalian chromosomes.
    EMBO J. 1997 Jun 16;16(12):3705-14 PMID: 9218811
  44. Telomere length regulation: getting the measure of chromosome ends.
    Biol Chem. 1997 Jul;378(7):591-7 PMID: 9278138
  45. Three Ever Shorter Telomere (EST) genes are dispensable for in vitro yeast telomerase activity.
    Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11190-5 PMID: 9326584
  46. Normal human chromosomes have long G-rich telomeric overhangs at one end.
    Genes Dev. 1997 Nov 1;11(21):2801-9 PMID: 9353250
  47. Telomerase activity, cell proliferation, and cancer.
    Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):90-2 PMID: 9419332
  48. TRF2 protects human telomeres from end-to-end fusions.
    Cell. 1998 Feb 6;92(3):401-13 PMID: 9476899
  49. Telomeres and senescence: the history, the experiment, the future.
    Curr Biol. 1998 Feb 26;8(5):R178-81 PMID: 9501064
  50. Effect of DNA secondary structure on human telomerase activity.
    Biochemistry. 1998 Apr 21;37(16):5536-41 PMID: 9548937
  51. The telomerase reverse transcriptase: components and regulation.
    Genes Dev. 1998 Apr 15;12(8):1073-85 PMID: 9553037
  52. The human HNRPD locus maps to 4q21 and encodes a highly conserved protein.
    Genomics. 1998 May 1;49(3):378-84 PMID: 9615222
  53. Telomere elongation by hnRNP A1 and a derivative that interacts with telomeric repeats and telomerase.
    Nat Genet. 1998 Jun;19(2):199-202 PMID: 9620782
  54. Regulated tissue-specific expression of antagonistic pre-mRNA splicing factors.
    RNA. 1998 Apr;4(4):430-44 PMID: 9630249
  55. Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs.
    EMBO J. 1998 Jun 15;17(12):3448-60 PMID: 9628880
  56. A hairpin conformation for the 3' overhang of Oxytricha nova telomeric DNA.
    J Mol Biol. 1998 Aug 14;281(2):261-70 PMID: 9698547
  57. Widespread presence in mammals and high binding specificity of a nuclear protein that recognises the single-stranded telomeric motif (CCCTAA)n.
    Eur J Biochem. 1998 Nov 15;258(1):93-9 PMID: 9851696
  58. G4 DNA binding by LR1 and its subunits, nucleolin and hnRNP D, A role for G-G pairing in immunoglobulin switch recombination.
    J Biol Chem. 1999 Jan 8;274(2):1066-71 PMID: 9873052
  59. Control of mRNA decay by heat shock-ubiquitin-proteasome pathway.
    Science. 1999 Apr 16;284(5413):499-502 PMID: 10205060
  60. Crystal structure of the two-RRM domain of hnRNP A1 (UP1) complexed with single-stranded telomeric DNA.
    Genes Dev. 1999 May 1;13(9):1102-15 PMID: 10323862
  61. Mammalian telomeres end in a large duplex loop.
    Cell. 1999 May 14;97(4):503-14 PMID: 10338214
  62. Telomerase and the maintenance of chromosome ends.
    Curr Opin Cell Biol. 1999 Jun;11(3):318-24 PMID: 10395557
  63. hnRNP complexes: composition, structure, and function.
    Curr Opin Cell Biol. 1999 Jun;11(3):363-71 PMID: 10395553
  64. Unraveling a cytoplasmic role for hnRNP D in the in vivo mRNA destabilization directed by the AU-rich element.
    Genes Dev. 1999 Jul 15;13(14):1884-97 PMID: 10421639
  65. Conserved structures and diversity of functions of RNA-binding proteins.
    Science. 1994 Jul 29;265(5172):615-21 PMID: 8036511
  66. G-quartet structures in telomeric DNA.
    Annu Rev Biophys Biomol Struct. 1994;23:703-30 PMID: 7919797
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.20.15.5425-5432.2000
Published
2000-08-00
Pages
5425-32
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC85994
Subset
IM
Grants
NCI NIH HHS · P01 CA016038 · United States
NIGMS NIH HHS · T32 GM007223 · United States
PHS HHS · P01 16038 · United States
NIGMS NIH HHS · T32 GM07223 · United States
External Links
PubMed source DOI: 10.1128/MCB.20.15.5425-5432.2000 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2