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. 1999 Mar 15;18(6):1526–1538. doi: 10.1093/emboj/18.6.1526

Specific destruction of kinetochore protein CENP-C and disruption of cell division by herpes simplex virus immediate-early protein Vmw110.

R D Everett 1, W C Earnshaw 1, J Findlay 1, P Lomonte 1
PMCID: PMC1171241  PMID: 10075924

Abstract

Examination of cells at the early stages of herpes simplex virus type 1 infection revealed that the viral immediate-early protein Vmw110 (also known as ICP0) formed discrete punctate accumulations associated with centromeres in both mitotic and interphase cells. The RING finger domain of Vmw110 (but not the C-terminal region) was essential for its localization at centromeres, thus distinguishing the Vmw110 sequences required for centromere association from those required for its localization at other discrete nuclear structures known as ND10, promyelocytic leukaemia (PML) bodies or PODs. We have shown recently that Vmw110 can induce the proteasome-dependent loss of several cellular proteins, including a number of probable SUMO-1-conjugated isoforms of PML, and this results in the disruption of ND10. In this study, we found some striking similarities between the interactions of Vmw110 with ND10 and centromeres. Specifically, centromeric protein CENP-C was lost from centromeres during virus infection in a Vmw110- and proteasome-dependent manner, causing substantial ultrastructural changes in the kinetochore. In consequence, dividing cells either became stalled in mitosis or underwent an unusual cytokinesis resulting in daughter cells with many micronuclei. These results emphasize the importance of CENP-C for mitotic progression and suggest that Vmw110 may be interfering with biochemical mechanisms which are relevant to both centromeres and ND10.

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Selected References

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  1. Bernat R. L., Borisy G. G., Rothfield N. F., Earnshaw W. C. Injection of anticentromere antibodies in interphase disrupts events required for chromosome movement at mitosis. J Cell Biol. 1990 Oct;111(4):1519–1533. doi: 10.1083/jcb.111.4.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Boddy M. N., Howe K., Etkin L. D., Solomon E., Freemont P. S. PIC 1, a novel ubiquitin-like protein which interacts with the PML component of a multiprotein complex that is disrupted in acute promyelocytic leukaemia. Oncogene. 1996 Sep 5;13(5):971–982. [PubMed] [Google Scholar]
  3. Cooke C. A., Bernat R. L., Earnshaw W. C. CENP-B: a major human centromere protein located beneath the kinetochore. J Cell Biol. 1990 May;110(5):1475–1488. doi: 10.1083/jcb.110.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Dyck J. A., Maul G. G., Miller W. H., Jr, Chen J. D., Kakizuka A., Evans R. M. A novel macromolecular structure is a target of the promyelocyte-retinoic acid receptor oncoprotein. Cell. 1994 Jan 28;76(2):333–343. doi: 10.1016/0092-8674(94)90340-9. [DOI] [PubMed] [Google Scholar]
  5. Earnshaw W. C., Rothfield N. Identification of a family of human centromere proteins using autoimmune sera from patients with scleroderma. Chromosoma. 1985;91(3-4):313–321. doi: 10.1007/BF00328227. [DOI] [PubMed] [Google Scholar]
  6. Eissenberg J. C., James T. C., Foster-Hartnett D. M., Hartnett T., Ngan V., Elgin S. C. Mutation in a heterochromatin-specific chromosomal protein is associated with suppression of position-effect variegation in Drosophila melanogaster. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9923–9927. doi: 10.1073/pnas.87.24.9923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Eissenberg J. C., Morris G. D., Reuter G., Hartnett T. The heterochromatin-associated protein HP-1 is an essential protein in Drosophila with dosage-dependent effects on position-effect variegation. Genetics. 1992 Jun;131(2):345–352. doi: 10.1093/genetics/131.2.345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Elgin S. C. Heterochromatin and gene regulation in Drosophila. Curr Opin Genet Dev. 1996 Apr;6(2):193–202. doi: 10.1016/s0959-437x(96)80050-5. [DOI] [PubMed] [Google Scholar]
  9. Everett R. D. Construction and characterization of herpes simplex virus type 1 mutants with defined lesions in immediate early gene 1. J Gen Virol. 1989 May;70(Pt 5):1185–1202. doi: 10.1099/0022-1317-70-5-1185. [DOI] [PubMed] [Google Scholar]
  10. Everett R. D., Cross A., Orr A. A truncated form of herpes simplex virus type 1 immediate-early protein Vmw110 is expressed in a cell type dependent manner. Virology. 1993 Dec;197(2):751–756. doi: 10.1006/viro.1993.1651. [DOI] [PubMed] [Google Scholar]
  11. Everett R. D., Freemont P., Saitoh H., Dasso M., Orr A., Kathoria M., Parkinson J. The disruption of ND10 during herpes simplex virus infection correlates with the Vmw110- and proteasome-dependent loss of several PML isoforms. J Virol. 1998 Aug;72(8):6581–6591. doi: 10.1128/jvi.72.8.6581-6591.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Everett R. D., Maul G. G. HSV-1 IE protein Vmw110 causes redistribution of PML. EMBO J. 1994 Nov 1;13(21):5062–5069. doi: 10.1002/j.1460-2075.1994.tb06835.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Everett R. D., Meredith M., Orr A., Cross A., Kathoria M., Parkinson J. A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J. 1997 Apr 1;16(7):1519–1530. doi: 10.1093/emboj/16.7.1519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Everett R. D., Meredith M., Orr A. The ability of herpes simplex virus type 1 immediate-early protein Vmw110 to bind to a ubiquitin-specific protease contributes to its roles in the activation of gene expression and stimulation of virus replication. J Virol. 1999 Jan;73(1):417–426. doi: 10.1128/jvi.73.1.417-426.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Everett R. D., Orr A., Preston C. M. A viral activator of gene expression functions via the ubiquitin-proteasome pathway. EMBO J. 1998 Dec 15;17(24):7161–7169. doi: 10.1093/emboj/17.24.7161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Fukagawa T., Brown W. R. Efficient conditional mutation of the vertebrate CENP-C gene. Hum Mol Genet. 1997 Dec;6(13):2301–2308. doi: 10.1093/hmg/6.13.2301. [DOI] [PubMed] [Google Scholar]
  17. Goddard A. D., Borrow J., Freemont P. S., Solomon E. Characterization of a zinc finger gene disrupted by the t(15;17) in acute promyelocytic leukemia. Science. 1991 Nov 29;254(5036):1371–1374. doi: 10.1126/science.1720570. [DOI] [PubMed] [Google Scholar]
  18. James T. C., Eissenberg J. C., Craig C., Dietrich V., Hobson A., Elgin S. C. Distribution patterns of HP1, a heterochromatin-associated nonhistone chromosomal protein of Drosophila. Eur J Cell Biol. 1989 Oct;50(1):170–180. [PubMed] [Google Scholar]
  19. Johnson P. A., Wang M. J., Friedmann T. Improved cell survival by the reduction of immediate-early gene expression in replication-defective mutants of herpes simplex virus type 1 but not by mutation of the virion host shutoff function. J Virol. 1994 Oct;68(10):6347–6362. doi: 10.1128/jvi.68.10.6347-6362.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kakizuka A., Miller W. H., Jr, Umesono K., Warrell R. P., Jr, Frankel S. R., Murty V. V., Dmitrovsky E., Evans R. M. Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RAR alpha with a novel putative transcription factor, PML. Cell. 1991 Aug 23;66(4):663–674. doi: 10.1016/0092-8674(91)90112-c. [DOI] [PubMed] [Google Scholar]
  21. Kalitsis P., Fowler K. J., Earle E., Hill J., Choo K. H. Targeted disruption of mouse centromere protein C gene leads to mitotic disarray and early embryo death. Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1136–1141. doi: 10.1073/pnas.95.3.1136. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kamitani T., Nguyen H. P., Kito K., Fukuda-Kamitani T., Yeh E. T. Covalent modification of PML by the sentrin family of ubiquitin-like proteins. J Biol Chem. 1998 Feb 6;273(6):3117–3120. doi: 10.1074/jbc.273.6.3117. [DOI] [PubMed] [Google Scholar]
  23. Kastner P., Perez A., Lutz Y., Rochette-Egly C., Gaub M. P., Durand B., Lanotte M., Berger R., Chambon P. Structure, localization and transcriptional properties of two classes of retinoic acid receptor alpha fusion proteins in acute promyelocytic leukemia (APL): structural similarities with a new family of oncoproteins. EMBO J. 1992 Feb;11(2):629–642. doi: 10.1002/j.1460-2075.1992.tb05095.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Koken M. H., Puvion-Dutilleul F., Guillemin M. C., Viron A., Linares-Cruz G., Stuurman N., de Jong L., Szostecki C., Calvo F., Chomienne C. The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion. EMBO J. 1994 Mar 1;13(5):1073–1083. doi: 10.1002/j.1460-2075.1994.tb06356.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lees-Miller S. P., Long M. C., Kilvert M. A., Lam V., Rice S. A., Spencer C. A. Attenuation of DNA-dependent protein kinase activity and its catalytic subunit by the herpes simplex virus type 1 transactivator ICP0. J Virol. 1996 Nov;70(11):7471–7477. doi: 10.1128/jvi.70.11.7471-7477.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lehming N., Le Saux A., Schüller J., Ptashne M. Chromatin components as part of a putative transcriptional repressing complex. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7322–7326. doi: 10.1073/pnas.95.13.7322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Maul G. G., Everett R. D. The nuclear location of PML, a cellular member of the C3HC4 zinc-binding domain protein family, is rearranged during herpes simplex virus infection by the C3HC4 viral protein ICP0. J Gen Virol. 1994 Jun;75(Pt 6):1223–1233. doi: 10.1099/0022-1317-75-6-1223. [DOI] [PubMed] [Google Scholar]
  28. Maul G. G., Guldner H. H., Spivack J. G. Modification of discrete nuclear domains induced by herpes simplex virus type 1 immediate early gene 1 product (ICP0). J Gen Virol. 1993 Dec;74(Pt 12):2679–2690. doi: 10.1099/0022-1317-74-12-2679. [DOI] [PubMed] [Google Scholar]
  29. Maul G. G., Ishov A. M., Everett R. D. Nuclear domain 10 as preexisting potential replication start sites of herpes simplex virus type-1. Virology. 1996 Mar 1;217(1):67–75. doi: 10.1006/viro.1996.0094. [DOI] [PubMed] [Google Scholar]
  30. Maul G. G. Nuclear domain 10, the site of DNA virus transcription and replication. Bioessays. 1998 Aug;20(8):660–667. doi: 10.1002/(SICI)1521-1878(199808)20:8<660::AID-BIES9>3.0.CO;2-M. [DOI] [PubMed] [Google Scholar]
  31. Meluh P. B., Koshland D. Evidence that the MIF2 gene of Saccharomyces cerevisiae encodes a centromere protein with homology to the mammalian centromere protein CENP-C. Mol Biol Cell. 1995 Jul;6(7):793–807. doi: 10.1091/mbc.6.7.793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Meredith M., Orr A., Elliott M., Everett R. Separation of sequence requirements for HSV-1 Vmw110 multimerisation and interaction with a 135-kDa cellular protein. Virology. 1995 May 10;209(1):174–187. doi: 10.1006/viro.1995.1241. [DOI] [PubMed] [Google Scholar]
  33. Müller S., Matunis M. J., Dejean A. Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus. EMBO J. 1998 Jan 2;17(1):61–70. doi: 10.1093/emboj/17.1.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Pandolfi P. P., Alcalay M., Fagioli M., Zangrilli D., Mencarelli A., Diverio D., Biondi A., Lo Coco F., Rambaldi A., Grignani F. Genomic variability and alternative splicing generate multiple PML/RAR alpha transcripts that encode aberrant PML proteins and PML/RAR alpha isoforms in acute promyelocytic leukaemia. EMBO J. 1992 Apr;11(4):1397–1407. doi: 10.1002/j.1460-2075.1992.tb05185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Parkinson J., Lees-Miller S. P., Everett R. D. Herpes simplex virus type 1 immediate-early protein vmw110 induces the proteasome-dependent degradation of the catalytic subunit of DNA-dependent protein kinase. J Virol. 1999 Jan;73(1):650–657. doi: 10.1128/jvi.73.1.650-657.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Pluta A. F., Earnshaw W. C., Goldberg I. G. Interphase-specific association of intrinsic centromere protein CENP-C with HDaxx, a death domain-binding protein implicated in Fas-mediated cell death. J Cell Sci. 1998 Jul 30;111(Pt 14):2029–2041. doi: 10.1242/jcs.111.14.2029. [DOI] [PubMed] [Google Scholar]
  37. Pluta A. F., Mackay A. M., Ainsztein A. M., Goldberg I. G., Earnshaw W. C. The centromere: hub of chromosomal activities. Science. 1995 Dec 8;270(5242):1591–1594. doi: 10.1126/science.270.5242.1591. [DOI] [PubMed] [Google Scholar]
  38. Preston C. M., Nicholl M. J. Repression of gene expression upon infection of cells with herpes simplex virus type 1 mutants impaired for immediate-early protein synthesis. J Virol. 1997 Oct;71(10):7807–7813. doi: 10.1128/jvi.71.10.7807-7813.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Saitoh H., Tomkiel J., Cooke C. A., Ratrie H., 3rd, Maurer M., Rothfield N. F., Earnshaw W. C. CENP-C, an autoantigen in scleroderma, is a component of the human inner kinetochore plate. Cell. 1992 Jul 10;70(1):115–125. doi: 10.1016/0092-8674(92)90538-n. [DOI] [PubMed] [Google Scholar]
  40. Samaniego L. A., Neiderhiser L., DeLuca N. A. Persistence and expression of the herpes simplex virus genome in the absence of immediate-early proteins. J Virol. 1998 Apr;72(4):3307–3320. doi: 10.1128/jvi.72.4.3307-3320.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Saunders W. S., Chue C., Goebl M., Craig C., Clark R. F., Powers J. A., Eissenberg J. C., Elgin S. C., Rothfield N. F., Earnshaw W. C. Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity. J Cell Sci. 1993 Feb;104(Pt 2):573–582. doi: 10.1242/jcs.104.2.573. [DOI] [PubMed] [Google Scholar]
  42. Seeler J. S., Marchio A., Sitterlin D., Transy C., Dejean A. Interaction of SP100 with HP1 proteins: a link between the promyelocytic leukemia-associated nuclear bodies and the chromatin compartment. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7316–7321. doi: 10.1073/pnas.95.13.7316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Sternsdorf T., Grötzinger T., Jensen K., Will H. Nuclear dots: actors on many stages. Immunobiology. 1997 Dec;198(1-3):307–331. doi: 10.1016/S0171-2985(97)80051-4. [DOI] [PubMed] [Google Scholar]
  44. Sternsdorf T., Jensen K., Will H. Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1. J Cell Biol. 1997 Dec 29;139(7):1621–1634. doi: 10.1083/jcb.139.7.1621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Stow N. D., Stow E. C. Isolation and characterization of a herpes simplex virus type 1 mutant containing a deletion within the gene encoding the immediate early polypeptide Vmw110. J Gen Virol. 1986 Dec;67(Pt 12):2571–2585. doi: 10.1099/0022-1317-67-12-2571. [DOI] [PubMed] [Google Scholar]
  46. Tomkiel J., Cooke C. A., Saitoh H., Bernat R. L., Earnshaw W. C. CENP-C is required for maintaining proper kinetochore size and for a timely transition to anaphase. J Cell Biol. 1994 May;125(3):531–545. doi: 10.1083/jcb.125.3.531. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Weis K., Rambaud S., Lavau C., Jansen J., Carvalho T., Carmo-Fonseca M., Lamond A., Dejean A. Retinoic acid regulates aberrant nuclear localization of PML-RAR alpha in acute promyelocytic leukemia cells. Cell. 1994 Jan 28;76(2):345–356. doi: 10.1016/0092-8674(94)90341-7. [DOI] [PubMed] [Google Scholar]
  48. Wu N., Watkins S. C., Schaffer P. A., DeLuca N. A. Prolonged gene expression and cell survival after infection by a herpes simplex virus mutant defective in the immediate-early genes encoding ICP4, ICP27, and ICP22. J Virol. 1996 Sep;70(9):6358–6369. doi: 10.1128/jvi.70.9.6358-6369.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yang X., Khosravi-Far R., Chang H. Y., Baltimore D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 1997 Jun 27;89(7):1067–1076. doi: 10.1016/s0092-8674(00)80294-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Yoshida H., Kitamura K., Tanaka K., Omura S., Miyazaki T., Hachiya T., Ohno R., Naoe T. Accelerated degradation of PML-retinoic acid receptor alpha (PML-RARA) oncoprotein by all-trans-retinoic acid in acute promyelocytic leukemia: possible role of the proteasome pathway. Cancer Res. 1996 Jul 1;56(13):2945–2948. [PubMed] [Google Scholar]
  51. de Thé H., Lavau C., Marchio A., Chomienne C., Degos L., Dejean A. The PML-RAR alpha fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell. 1991 Aug 23;66(4):675–684. doi: 10.1016/0092-8674(91)90113-d. [DOI] [PubMed] [Google Scholar]

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