Abstract
Terminal deletions of a Drosophila minichromosome (Dp(1;f)1187) dramatically increase the position effect variegation (PEV) of a yellow(+) body-color gene located in cis. Such terminal deficiency-associated PEV (TDA-PEV) can be suppressed by the presence of a second minichromosome, a phenomenon termed "trans-suppression." We performed a screen for mutations that modify TDA-PEV and trans-suppression. Seventy suppressors and enhancers of TDA-PEV were identified, but no modifiers of trans-suppression were recovered. Secondary analyses of the effects of these mutations on different PEV types identified 10 mutations that modify only TDA-PEV and 6 mutations that modify TDA-PEV and only one other type of PEV. One mutation, a new allele of Su(var)3-9, affects all forms of PEV, including silencing associated with the insertion of a transgene into telomeric regions (TPE). This Su(var)3-9 allele is the first modifier of PEV to affect TPE and provides a unique link between different types of gene silencing in Drosophila. The remaining mutations affected multiple PEV types, indicating that general PEV modifiers impact TDA-PEV. Modifiers of TDA-PEV may identify proteins that play important roles in general heterochromatin biology, including proteins involved in telomere structure and function and the organization of chromosomes in the interphase nucleus.
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- Aagaard L., Laible G., Selenko P., Schmid M., Dorn R., Schotta G., Kuhfittig S., Wolf A., Lebersorger A., Singh P. B. Functional mammalian homologues of the Drosophila PEV-modifier Su(var)3-9 encode centromere-associated proteins which complex with the heterochromatin component M31. EMBO J. 1999 Apr 1;18(7):1923–1938. doi: 10.1093/emboj/18.7.1923. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ahmad K., Golic K. G. Telomere loss in somatic cells of Drosophila causes cell cycle arrest and apoptosis. Genetics. 1999 Mar;151(3):1041–1051. doi: 10.1093/genetics/151.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Aramayo R., Metzenberg R. L. Meiotic transvection in fungi. Cell. 1996 Jul 12;86(1):103–113. doi: 10.1016/s0092-8674(00)80081-1. [DOI] [PubMed] [Google Scholar]
- Bannister A. J., Zegerman P., Partridge J. F., Miska E. A., Thomas J. O., Allshire R. C., Kouzarides T. Selective recognition of methylated lysine 9 on histone H3 by the HP1 chromo domain. Nature. 2001 Mar 1;410(6824):120–124. doi: 10.1038/35065138. [DOI] [PubMed] [Google Scholar]
- Biessmann H., Carter S. B., Mason J. M. Chromosome ends in Drosophila without telomeric DNA sequences. Proc Natl Acad Sci U S A. 1990 Mar;87(5):1758–1761. doi: 10.1073/pnas.87.5.1758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Biessmann H., Mason J. M. Telomere maintenance without telomerase. Chromosoma. 1997 Jul;106(2):63–69. doi: 10.1007/s004120050225. [DOI] [PubMed] [Google Scholar]
- Blasco M. A., Lee H. W., Hande M. P., Samper E., Lansdorp P. M., DePinho R. A., Greider C. W. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell. 1997 Oct 3;91(1):25–34. doi: 10.1016/s0092-8674(01)80006-4. [DOI] [PubMed] [Google Scholar]
- Bridger J. M., Bickmore W. A. Putting the genome on the map. Trends Genet. 1998 Oct;14(10):403–409. doi: 10.1016/s0168-9525(98)01572-8. [DOI] [PubMed] [Google Scholar]
- Comings D. E. Arrangement of chromatin in the nucleus. Hum Genet. 1980 Feb;53(2):131–143. doi: 10.1007/BF00273484. [DOI] [PubMed] [Google Scholar]
- Cooper J. P. Telomere transitions in yeast: the end of the chromosome as we know it. Curr Opin Genet Dev. 2000 Apr;10(2):169–177. doi: 10.1016/s0959-437x(00)00070-8. [DOI] [PubMed] [Google Scholar]
- Cryderman D. E., Morris E. J., Biessmann H., Elgin S. C., Wallrath L. L. Silencing at Drosophila telomeres: nuclear organization and chromatin structure play critical roles. EMBO J. 1999 Jul 1;18(13):3724–3735. doi: 10.1093/emboj/18.13.3724. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Csink A. K., Henikoff S. Genetic modification of heterochromatic association and nuclear organization in Drosophila. Nature. 1996 Jun 6;381(6582):529–531. doi: 10.1038/381529a0. [DOI] [PubMed] [Google Scholar]
- Dernburg A. F., Broman K. W., Fung J. C., Marshall W. F., Philips J., Agard D. A., Sedat J. W. Perturbation of nuclear architecture by long-distance chromosome interactions. Cell. 1996 May 31;85(5):745–759. doi: 10.1016/s0092-8674(00)81240-4. [DOI] [PubMed] [Google Scholar]
- Dietzel S., Jauch A., Kienle D., Qu G., Holtgreve-Grez H., Eils R., Münkel C., Bittner M., Meltzer P. S., Trent J. M. Separate and variably shaped chromosome arm domains are disclosed by chromosome arm painting in human cell nuclei. Chromosome Res. 1998 Jan;6(1):25–33. doi: 10.1023/a:1009262223693. [DOI] [PubMed] [Google Scholar]
- Dobie K. W., Kennedy C. D., Velasco V. M., McGrath T. L., Weko J., Patterson R. W., Karpen G. H. Identification of chromosome inheritance modifiers in Drosophila melanogaster. Genetics. 2001 Apr;157(4):1623–1637. doi: 10.1093/genetics/157.4.1623. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Donaldson K. M., Karpen G. H. Trans-suppression of terminal deficiency-associated position effect variegation in a Drosophila minichromosome. Genetics. 1997 Feb;145(2):325–337. doi: 10.1093/genetics/145.2.325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dorn R., Szidonya J., Korge G., Sehnert M., Taubert H., Archoukieh E., Tschiersch B., Morawietz H., Wustmann G., Hoffmann G. P transposon-induced dominant enhancer mutations of position-effect variegation in Drosophila melanogaster. Genetics. 1993 Feb;133(2):279–290. doi: 10.1093/genetics/133.2.279. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Ekwall K., Cranston G., Allshire R. C. Fission yeast mutants that alleviate transcriptional silencing in centromeric flanking repeats and disrupt chromosome segregation. Genetics. 1999 Nov;153(3):1153–1169. doi: 10.1093/genetics/153.3.1153. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ekwall K., Javerzat J. P., Lorentz A., Schmidt H., Cranston G., Allshire R. The chromodomain protein Swi6: a key component at fission yeast centromeres. Science. 1995 Sep 8;269(5229):1429–1431. doi: 10.1126/science.7660126. [DOI] [PubMed] [Google Scholar]
- Ekwall K., Nimmo E. R., Javerzat J. P., Borgstrøm B., Egel R., Cranston G., Allshire R. Mutations in the fission yeast silencing factors clr4+ and rik1+ disrupt the localisation of the chromo domain protein Swi6p and impair centromere function. J Cell Sci. 1996 Nov;109(Pt 11):2637–2648. doi: 10.1242/jcs.109.11.2637. [DOI] [PubMed] [Google Scholar]
- Fanti L., Giovinazzo G., Berloco M., Pimpinelli S. The heterochromatin protein 1 prevents telomere fusions in Drosophila. Mol Cell. 1998 Nov;2(5):527–538. doi: 10.1016/s1097-2765(00)80152-5. [DOI] [PubMed] [Google Scholar]
- Funabiki H., Hagan I., Uzawa S., Yanagida M. Cell cycle-dependent specific positioning and clustering of centromeres and telomeres in fission yeast. J Cell Biol. 1993 Jun;121(5):961–976. doi: 10.1083/jcb.121.5.961. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gottschling D. E., Aparicio O. M., Billington B. L., Zakian V. A. Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell. 1990 Nov 16;63(4):751–762. doi: 10.1016/0092-8674(90)90141-z. [DOI] [PubMed] [Google Scholar]
- Grigliatti T. Position-effect variegation--an assay for nonhistone chromosomal proteins and chromatin assembly and modifying factors. Methods Cell Biol. 1991;35:587–627. [PubMed] [Google Scholar]
- Hari K. L., Cook K. R., Karpen G. H. The Drosophila Su(var)2-10 locus regulates chromosome structure and function and encodes a member of the PIAS protein family. Genes Dev. 2001 Jun 1;15(11):1334–1348. doi: 10.1101/gad.877901. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Henikoff S. Nuclear organization and gene expression: homologous pairing and long-range interactions. Curr Opin Cell Biol. 1997 Jun;9(3):388–395. doi: 10.1016/s0955-0674(97)80012-9. [DOI] [PubMed] [Google Scholar]
- Hochstrasser M., Mathog D., Gruenbaum Y., Saumweber H., Sedat J. W. Spatial organization of chromosomes in the salivary gland nuclei of Drosophila melanogaster. J Cell Biol. 1986 Jan;102(1):112–123. doi: 10.1083/jcb.102.1.112. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ivanova A. V., Bonaduce M. J., Ivanov S. V., Klar A. J. The chromo and SET domains of the Clr4 protein are essential for silencing in fission yeast. Nat Genet. 1998 Jun;19(2):192–195. doi: 10.1038/566. [DOI] [PubMed] [Google Scholar]
- 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]
- Karpen G. H. Position-effect variegation and the new biology of heterochromatin. Curr Opin Genet Dev. 1994 Apr;4(2):281–291. doi: 10.1016/s0959-437x(05)80055-3. [DOI] [PubMed] [Google Scholar]
- Karpen G. H., Spradling A. C. Analysis of subtelomeric heterochromatin in the Drosophila minichromosome Dp1187 by single P element insertional mutagenesis. Genetics. 1992 Nov;132(3):737–753. doi: 10.1093/genetics/132.3.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurenova E., Champion L., Biessmann H., Mason J. M. Directional gene silencing induced by a complex subtelomeric satellite from Drosophila. Chromosoma. 1998 Nov;107(5):311–320. doi: 10.1007/s004120050313. [DOI] [PubMed] [Google Scholar]
- LaSalle J. M., Lalande M. Homologous association of oppositely imprinted chromosomal domains. Science. 1996 May 3;272(5262):725–728. doi: 10.1126/science.272.5262.725. [DOI] [PubMed] [Google Scholar]
- Lachner M., O'Carroll D., Rea S., Mechtler K., Jenuwein T. Methylation of histone H3 lysine 9 creates a binding site for HP1 proteins. Nature. 2001 Mar 1;410(6824):116–120. doi: 10.1038/35065132. [DOI] [PubMed] [Google Scholar]
- Lamond A. I., Earnshaw W. C. Structure and function in the nucleus. Science. 1998 Apr 24;280(5363):547–553. doi: 10.1126/science.280.5363.547. [DOI] [PubMed] [Google Scholar]
- Laroche T., Martin S. G., Gotta M., Gorham H. C., Pryde F. E., Louis E. J., Gasser S. M. Mutation of yeast Ku genes disrupts the subnuclear organization of telomeres. Curr Biol. 1998 May 21;8(11):653–656. doi: 10.1016/s0960-9822(98)70252-0. [DOI] [PubMed] [Google Scholar]
- Le M. H., Duricka D., Karpen G. H. Islands of complex DNA are widespread in Drosophila centric heterochromatin. Genetics. 1995 Sep;141(1):283–303. doi: 10.1093/genetics/141.1.283. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Leitch A. R. Higher levels of organization in the interphase nucleus of cycling and differentiated cells. Microbiol Mol Biol Rev. 2000 Mar;64(1):138–152. doi: 10.1128/mmbr.64.1.138-152.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Levis R. W., Ganesan R., Houtchens K., Tolar L. A., Sheen F. M. Transposons in place of telomeric repeats at a Drosophila telomere. Cell. 1993 Dec 17;75(6):1083–1093. doi: 10.1016/0092-8674(93)90318-k. [DOI] [PubMed] [Google Scholar]
- Levis R. W. Viable deletions of a telomere from a Drosophila chromosome. Cell. 1989 Aug 25;58(4):791–801. doi: 10.1016/0092-8674(89)90112-8. [DOI] [PubMed] [Google Scholar]
- Levis R., Hazelrigg T., Rubin G. M. Effects of genomic position on the expression of transduced copies of the white gene of Drosophila. Science. 1985 Aug 9;229(4713):558–561. doi: 10.1126/science.2992080. [DOI] [PubMed] [Google Scholar]
- Locke J., Kotarski M. A., Tartof K. D. Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect. Genetics. 1988 Sep;120(1):181–198. doi: 10.1093/genetics/120.1.181. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Lustig A. J. Mechanisms of silencing in Saccharomyces cerevisiae. Curr Opin Genet Dev. 1998 Apr;8(2):233–239. doi: 10.1016/s0959-437x(98)80146-9. [DOI] [PubMed] [Google Scholar]
- Mason J. M., Strobel E., Green M. M. mu-2: mutator gene in Drosophila that potentiates the induction of terminal deficiencies. Proc Natl Acad Sci U S A. 1984 Oct;81(19):6090–6094. doi: 10.1073/pnas.81.19.6090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mathog D., Hochstrasser M., Gruenbaum Y., Saumweber H., Sedat J. Characteristic folding pattern of polytene chromosomes in Drosophila salivary gland nuclei. 1984 Mar 29-Apr 4Nature. 308(5958):414–421. doi: 10.1038/308414a0. [DOI] [PubMed] [Google Scholar]
- McEachern M. J., Krauskopf A., Blackburn E. H. Telomeres and their control. Annu Rev Genet. 2000;34:331–358. doi: 10.1146/annurev.genet.34.1.331. [DOI] [PubMed] [Google Scholar]
- Morris J. R., Chen J., Filandrinos S. T., Dunn R. C., Fisk R., Geyer P. K., Wu C. An analysis of transvection at the yellow locus of Drosophila melanogaster. Genetics. 1999 Feb;151(2):633–651. doi: 10.1093/genetics/151.2.633. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nimmo E. R., Pidoux A. L., Perry P. E., Allshire R. C. Defective meiosis in telomere-silencing mutants of Schizosaccharomyces pombe. Nature. 1998 Apr 23;392(6678):825–828. doi: 10.1038/33941. [DOI] [PubMed] [Google Scholar]
- O'Carroll D., Scherthan H., Peters A. H., Opravil S., Haynes A. R., Laible G., Rea S., Schmid M., Lebersorger A., Jerratsch M. Isolation and characterization of Suv39h2, a second histone H3 methyltransferase gene that displays testis-specific expression. Mol Cell Biol. 2000 Dec;20(24):9423–9433. doi: 10.1128/mcb.20.24.9423-9433.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pardue M. L., DeBaryshe P. G. Telomeres and telomerase: more than the end of the line. Chromosoma. 1999 May;108(2):73–82. doi: 10.1007/s004120050354. [DOI] [PubMed] [Google Scholar]
- Platero J. S., Csink A. K., Quintanilla A., Henikoff S. Changes in chromosomal localization of heterochromatin-binding proteins during the cell cycle in Drosophila. J Cell Biol. 1998 Mar 23;140(6):1297–1306. doi: 10.1083/jcb.140.6.1297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reuter G., Wolff I. Isolation of dominant suppressor mutations for position-effect variegation in Drosophila melanogaster. Mol Gen Genet. 1981;182(3):516–519. doi: 10.1007/BF00293947. [DOI] [PubMed] [Google Scholar]
- Rudolph K. L., Chang S., Lee H. W., Blasco M., Gottlieb G. J., Greider C., DePinho R. A. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell. 1999 Mar 5;96(5):701–712. doi: 10.1016/s0092-8674(00)80580-2. [DOI] [PubMed] [Google Scholar]
- Saitoh S., Takahashi K., Yanagida M. Mis6, a fission yeast inner centromere protein, acts during G1/S and forms specialized chromatin required for equal segregation. Cell. 1997 Jul 11;90(1):131–143. doi: 10.1016/s0092-8674(00)80320-7. [DOI] [PubMed] [Google Scholar]
- Sass G. L., Henikoff S. Comparative analysis of position-effect variegation mutations in Drosophila melanogaster delineates the targets of modifiers. Genetics. 1998 Feb;148(2):733–741. doi: 10.1093/genetics/148.2.733. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sinclair D. A., Ruddell A. A., Brock J. K., Clegg N. J., Lloyd V. K., Grigliatti T. A. A cytogenetic and genetic characterization of a group of closely linked second chromosome mutations that suppress position-effect variegation in Drosophila melanogaster. Genetics. 1992 Feb;130(2):333–344. doi: 10.1093/genetics/130.2.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Talbert P. B., LeCiel C. D., Henikoff S. Modification of the Drosophila heterochromatic mutation brownDominant by linkage alterations. Genetics. 1994 Feb;136(2):559–571. doi: 10.1093/genetics/136.2.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tartof K. D., Hobbs C., Jones M. A structural basis for variegating position effects. Cell. 1984 Jul;37(3):869–878. doi: 10.1016/0092-8674(84)90422-7. [DOI] [PubMed] [Google Scholar]
- Tower J., Karpen G. H., Craig N., Spradling A. C. Preferential transposition of Drosophila P elements to nearby chromosomal sites. Genetics. 1993 Feb;133(2):347–359. doi: 10.1093/genetics/133.2.347. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tschiersch B., Hofmann A., Krauss V., Dorn R., Korge G., Reuter G. The protein encoded by the Drosophila position-effect variegation suppressor gene Su(var)3-9 combines domains of antagonistic regulators of homeotic gene complexes. EMBO J. 1994 Aug 15;13(16):3822–3831. doi: 10.1002/j.1460-2075.1994.tb06693.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Visser A. E., Eils R., Jauch A., Little G., Bakker P. J., Cremer T., Aten J. A. Spatial distributions of early and late replicating chromatin in interphase chromosome territories. Exp Cell Res. 1998 Sep 15;243(2):398–407. doi: 10.1006/excr.1998.4144. [DOI] [PubMed] [Google Scholar]
- Wakimoto B. T., Hearn M. G. The effects of chromosome rearrangements on the expression of heterochromatic genes in chromosome 2L of Drosophila melanogaster. Genetics. 1990 May;125(1):141–154. doi: 10.1093/genetics/125.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wallrath L. L. Unfolding the mysteries of heterochromatin. Curr Opin Genet Dev. 1998 Apr;8(2):147–153. doi: 10.1016/s0959-437x(98)80135-4. [DOI] [PubMed] [Google Scholar]
- Wustmann G., Szidonya J., Taubert H., Reuter G. The genetics of position-effect variegation modifying loci in Drosophila melanogaster. Mol Gen Genet. 1989 Jun;217(2-3):520–527. doi: 10.1007/BF02464926. [DOI] [PubMed] [Google Scholar]
- Zink D., Cremer T., Saffrich R., Fischer R., Trendelenburg M. F., Ansorge W., Stelzer E. H. Structure and dynamics of human interphase chromosome territories in vivo. Hum Genet. 1998 Feb;102(2):241–251. doi: 10.1007/s004390050686. [DOI] [PubMed] [Google Scholar]
