Skip to main content
SpringerLink
Log in

Human DNA topoisomerase I: relaxation, roles, and damage control

  • Review
  • Published:
Chromosoma Aims and scope Submit manuscript

Abstract

Human DNA topoisomerase I is an essential enzyme involved in resolving the torsional stress associated with DNA replication, transcription, and chromatin condensation. The catalytic cycle of the enzyme consists of DNA cleavage to form a covalent enzyme–DNA intermediate, DNA relaxation, and finally, religation of the phosphate backbone to restore the continuity of the DNA. Structure/function studies have elucidated a flexible enzyme that relaxes DNA through coordinated, controlled movements of distinct enzyme domains. The cellular roles of topoisomerase I are apparent throughout the nucleus, but the concentration of processes acting on ribosomal DNA results in topoisomerase I accumulation in the nucleolus. Although the activity of topoisomerase I is required in these processes, the enzyme can also have a deleterious effect on cells. In the event that the final religation step of the reaction cycle is prevented, the covalent topoisomerase I–DNA intermediate becomes a toxic DNA lesion that must be repaired. The complexities of the relaxation reaction, the cellular roles, and the pathways that must exist to repair topoisomerase I-mediated DNA damage highlight the importance of continued study of this essential enzyme.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Alsner J, Svejstrup JQ, Kjeldsen E, Sorensen BS, Westergaard O (1992) Identification of an N-terminal domain of eukaryotic DNA topoisomerase I dispensable for catalytic activity but essential for in vivo function. J Biol Chem 267:12408–12411

    Google Scholar 

  • Arabi A, Rustum C, Hallberg E, Wright AP (2003) Accumulation of c-Myc and proteasomes at the nucleoli of cells containing elevated c-Myc protein levels. J Cell Sci 116:1707–1717

    Google Scholar 

  • Ayaydin F, Dasso M (2004) Distinct in vivo dynamics of vertebrate SUMO paralogues. Mol Biol Cell 15:5208–5218

    Google Scholar 

  • Baker SD, Wadkins RM, Stewart CF, Beck WT, Danks MK (1995) Cell cycle analysis of amount and distribution of nuclear DNA topoisomerase I as determined by fluorescence digital imaging microscopy. Cytometry 19:134–145

    Google Scholar 

  • Barrows LR, Holden JA, Anderson M, D’Arpa P (1998) The CHO XRCC1 mutant, EM9, deficient in DNA ligase III activity, exhibits hypersensitivity to camptothecin independent of DNA replication. Mutat Res 408:103–110

    Google Scholar 

  • Bauer PI, Buki KG, Comstock JA, Kun E (2000) Activation of topoisomerase I by poly [ADP-ribose] polymerase. Int J Mol Med 5:533–540

    Google Scholar 

  • Been MD, Burgess RR, Champoux JJ (1984) Nucleotide sequence preference at rat liver and wheat germ type 1 DNA topoisomerase breakage sites in duplex SV40 DNA. Nucleic Acids Res 12:3097–3114

    Google Scholar 

  • Bharti AK, Olson MO, Kufe DW, Rubin EH (1996) Identification of a nucleolin binding site in human topoisomerase I. J Biol Chem 271:P1993–P1997

    Google Scholar 

  • Bjornsti MA, Benedetti P, Viglianti GA, Wang JC (1989) Expression of human DNA topoisomerase I in yeast cells lacking yeast DNA topoisomerase I: restoration of sensitivity of the cells to the antitumor drug camptothecin. Cancer Res 49:6318–6323

    Google Scholar 

  • Bonven BJ, Gocke E, Westergaard O (1985) A high affinity topoisomerase I binding sequence is clustered at DNAase I hypersensitive sites in Tetrahymena R-chromatin. Cell 41:541–551

    Google Scholar 

  • Buckwalter CA, Lin AH, Tanizawa A, Pommier YG, Cheng YC, Kaufmann SH (1996) RNA synthesis inhibitors alter the subnuclear distribution of DNA topoisomerase I. Cancer Res 56:1674–1681

    Google Scholar 

  • Carey JF, Schultz SJ, Sisson L, Fazzio TG, Champoux JJ (2003) DNA relaxation by human topoisomerase I occurs in the closed clamp conformation of the protein. Proc Natl Acad Sci U S A 100:5640–5645

    Google Scholar 

  • Castano IB, Brzoska PM, Sadoff BU, Chen H, Christman MF (1996) Mitotic chromosome condensation in the rDNA requires TRF4 and DNA topoisomerase I in Saccharomyces cerevisiae. Genes Dev 10:2564–2576

    Google Scholar 

  • Catley L, Tai YT, Shringarpure R, Burger R, Son MT, Podar K, Tassone P, Chauhan D, Hideshima T, Denis L, Richardson P, Munshi NC, Anderson KC (2004) Proteasomal degradation of topoisomerase I is preceded by c-Jun NH2-terminal kinase activation, Fas up-regulation, and poly(ADP-ribose) polymerase cleavage in SN38-mediated cytotoxicity against multiple myeloma. Cancer Res 64:8746–8753

    Google Scholar 

  • Champoux J (1990) DNA topology and its biological effects. Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, pp 217–242

    Google Scholar 

  • Champoux JJ (2001) DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem 70:369–413

    Article  CAS  PubMed  Google Scholar 

  • Champoux JJ, Dulbecco R (1972) An activity from mammalian cells that untwists superhelical DNA—a possible swivel for DNA replication (polyoma–ethidium bromide–mouse–embryo cells–dye binding assay). Proc Natl Acad Sci U S A 69:143–146

    Google Scholar 

  • Chillemi G, Redinbo M, Bruselles A, Desideri A (2004) Role of the linker domain and the 203–214 N-terminal residues in the human topoisomerase I DNA complex dynamics. Biophys J 87:4087–4097

    Google Scholar 

  • Christensen MO, Barthelmes HU, Boege F, Mielke C (2002a) The N-terminal domain anchors human topoisomerase I at fibrillar centers of nucleoli and nucleolar organizer regions of mitotic chromosomes. J Biol Chem 277:35932–35938

    Google Scholar 

  • Christensen MO, Barthelmes HU, Feineis S, Knudsen BR, Andersen AH, Boege F, Mielke C (2002b) Changes in mobility account for camptothecin-induced subnuclear relocation of topoisomerase I. J Biol Chem 277:15661–15665

    Google Scholar 

  • Christensen MO, Barthelmes HU, Boege F, Mielke C (2003) Residues 190–210 of human topoisomerase I are required for enzyme activity in vivo but not in vitro. Nucleic Acids Res 31:7255–7263

    Google Scholar 

  • Christensen MO, Krokowski RM, Barthelmes HU, Hock R, Boege F, Mielke C (2004) Distinct effects of topoisomerase I and RNA polymerase I inhibitors suggest a dual mechanism of nucleolar/nucleoplasmic partitioning of topoisomerase I. J Biol Chem 279:21873–21882

    Google Scholar 

  • Connelly JC, Leach DR (2004) Repair of DNA covalently linked to protein. Mol Cell 13:307–316

    Google Scholar 

  • Danks MK, Garrett KE, Marion RC, Whipple DO (1996) Subcellular redistribution of DNA topoisomerase I in anaplastic astrocytoma cells treated with topotecan. Cancer Res 56:1664–1673

    Google Scholar 

  • Debethune L, Kohlhagen G, Grandas A, Pommier Y (2002) Processing of nucleopeptides mimicking the topoisomerase I–DNA covalent complex by tyrosyl–DNA phosphodiesterase. Nucleic Acids Res 30:1198–1204

    Google Scholar 

  • Desai SD, Liu LF, Vazquez-Abad D, D’Arpa P (1997) Ubiquitin-dependent destruction of topoisomerase I is stimulated by the antitumor drug camptothecin. J Biol Chem 272:24159–24164

    Google Scholar 

  • Desai SD, Zhang H, Rodriguez-Bauman A, Yang JM, Wu X, Gounder MK, Rubin EH, Liu LF (2003) Transcription-dependent degradation of topoisomerase I–DNA covalent complexes. Mol Cell Biol 23:2341–2350

    Google Scholar 

  • El-Khamisy SF, Saifi GM, Weinfeld M, Johansson F, Helleday T, Lupski JR, Caldecott KW (2005) Defective DNA single-strand break repair in spinocerebellar ataxia with axonal neuropathy-1. Nature 434:108–113

    Google Scholar 

  • Frohlich RF, Andersen FF, Westergaard O, Andersen AH, Knudsen BR (2004) Regions within the N-terminal domain of human topoisomerase I exert important functions during strand rotation and DNA binding. J Mol Biol 336:93–103

    Google Scholar 

  • Gao H, Chen XB, McGowan CH (2003) Mus81 endonuclease localizes to nucleoli and to regions of DNA damage in human S-phase cells. Mol Biol Cell 14:4826–4834

    Google Scholar 

  • Garcia-Carbonero R, Supko JG (2002) Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res 8:641–661

    Google Scholar 

  • Gobert C, Bracco L, Rossi F, Olivier M, Tazi J, Lavelle F, Larsen AK, Riou JF (1996) Modulation of DNA topoisomerase I activity by p53. Biochemistry 35:5778–5786

    Google Scholar 

  • Gonzalez IL, Sylvester JE (1995) Complete sequence of the 43-kb human ribosomal DNA repeat: analysis of the intergenic spacer. Genomics 27:320–328

    Google Scholar 

  • Haluska P Jr, Saleem A, Rasheed Z, Ahmed F, Su EW, Liu LF, Rubin EH (1999) Interaction between human topoisomerase I and a novel RING finger/arginine–serine protein. Nucleic Acids Res 27:2538–2544

    Google Scholar 

  • Hannan KM, Hannan RD, Rothblum LI (1998) Transcription by RNA polymerase I. Front Biosci 3:d376–d398

    Google Scholar 

  • Hsiang YH, Liu LF (1988) Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 48:1722–1726

    CAS  PubMed  Google Scholar 

  • Interthal H, Pouliot JJ, Champoux JJ (2001) The tyrosyl–DNA phosphodiesterase Tdp1 is a member of the phospholipase D superfamily. Proc Natl Acad Sci U S A 98:12009–12014

    Google Scholar 

  • Interthal H, Quigley PM, Hol WG, Champoux JJ (2004) The role of lysine 532 in the catalytic mechanism of human topoisomerase I. J Biol Chem 279:2984–2992

    Google Scholar 

  • Karayan L, Riou JF, Seite P, Migeon J, Cantereau A, Larsen CJ (2001) Human ARF protein interacts with topoisomerase I and stimulates its activity. Oncogene 20:836–848

    Google Scholar 

  • Kretzschmar M, Meisterernst M, Roeder RG (1993) Identification of human DNA topoisomerase I as a cofactor for activator-dependent transcription by RNA polymerase II. Proc Natl Acad Sci U S A 90:11508–11512

    Google Scholar 

  • Laine JP, Opresko PL, Indig FE, Harrigan JA, von Kobbe C, Bohr VA (2003) Werner protein stimulates topoisomerase I DNA relaxation activity. Cancer Res 63:7136–7146

    Google Scholar 

  • Lebel M, Spillare EA, Harris CC, Leder P (1999) The Werner syndrome gene product co-purifies with the DNA replication complex and interacts with PCNA and topoisomerase I. J Biol Chem 274:37795–37799

    Article  CAS  Google Scholar 

  • Lee MP, Brown SD, Chen A, Hsieh TS (1993) DNA topoisomerase I is essential in Drosophila melanogaster. Proc Natl Acad Sci U S A 90:6656–6660

    Google Scholar 

  • Leppard JB, Dong Z, Mackey ZB, Tomkinson AE (2003) Physical and functional interaction between DNA ligase IIIalpha and poly(ADP-ribose) polymerase 1 in DNA single-strand break repair. Mol Cell Biol 23:5919–5927

    Google Scholar 

  • Lesher DT, Pommier Y, Stewart L, Redinbo MR (2002) 8-Oxoguanine rearranges the active site of human topoisomerase I. Proc Natl Acad Sci U S A 99:12102–12107

    Google Scholar 

  • Li TK, Liu LF (2001) Tumor cell death induced by topoisomerase-targeting drugs. Annu Rev Pharmacol Toxicol 41:53–77

    Google Scholar 

  • Liu C, Pouliot JJ, Nash HA (2002) Repair of topoisomerase I covalent complexes in the absence of the tyrosyl–DNA phosphodiesterase Tdp1. Proc Natl Acad Sci U S A 99:14970–14975

    Google Scholar 

  • Madden KR, Stewart L, Champoux JJ (1995) Preferential binding of human topoisomerase I to superhelical DNA. EMBO J 14:5399–5409

    Google Scholar 

  • Mao Y, Muller MT (2003) Down modulation of topoisomerase I affects DNA repair efficiency. DNA Repair (Amst) 2:1115–1126

    Google Scholar 

  • Mao Y, Sun M, Desai SD, Liu LF (2000) SUMO-1 conjugation to topoisomerase I: a possible repair response to topoisomerase-mediated DNA damage. Proc Natl Acad Sci U S A 97:4046–4051

    Google Scholar 

  • Mao Y, Mehl IR, Muller MT (2002) Subnuclear distribution of topoisomerase I is linked to ongoing transcription and p53 status. Proc Natl Acad Sci U S A 99:1235–1240

    Google Scholar 

  • Meder VS, Boeglin M, de Murcia G, Schreiber V (2005) PARP-1 and PARP-2 interact with nucleophosmin/B23 and accumulate in transcriptionally active nucleoli. J Cell Sci 118:211–222

    Google Scholar 

  • Merino A, Madden KR, Lane WS, Champoux JJ, Reinberg D (1993) DNA topoisomerase I is involved in both repression and activation of transcription. Nature 365:227–232

    Google Scholar 

  • Mo YY, Wang C, Beck WT (2000) A novel nuclear localization signal in human DNA topoisomerase I. J Biol Chem 275:41107–41113

    Google Scholar 

  • Morham SG, Kluckman KD, Voulomanos N, Smithies O (1996) Targeted disruption of the mouse topoisomerase I gene by camptothecin selection. Mol Cell Biol 16:6804–6809

    Google Scholar 

  • Morris EJ, Geller HM (1996) Induction of neuronal apoptosis by camptothecin, an inhibitor of DNA topoisomerase-I: evidence for cell cycle-independent toxicity. J Cell Biol 134:757–770

    Google Scholar 

  • Muller MT, Pfund WP, Mehta VB, Trask DK (1985) Eukaryotic type I topoisomerase is enriched in the nucleolus and catalytically active on ribosomal DNA. EMBO J 4:1237–1243

    Google Scholar 

  • Okano S, Lan L, Caldecott KW, Mori T, Yasui A (2003) Spatial and temporal cellular responses to single-strand breaks in human cells. Mol Cell Biol 23:3974–3981

    Google Scholar 

  • Plo I, Liao ZY, Barcelo JM, Kohlhagen G, Caldecott KW, Weinfeld M, Pommier Y (2003) Association of XRCC1 and tyrosyl DNA phosphodiesterase (Tdp1) for the repair of topoisomerase I-mediated DNA lesions. DNA Repair (Amst) 2:1087–1100

    Google Scholar 

  • Pommier Y, Cherfils J (2005) Interfacial inhibition of macromolecular interactions: nature’s paradigm for drug discovery. Trends Pharmacol Sci 26:138–145

    Google Scholar 

  • Pommier Y, Pourquier P, Fan Y, Strumberg D (1998) Mechanism of action of eukaryotic DNA topoisomerase I and drugs targeted to the enzyme. Biochim Biophys Acta 1400:83–105

    Article  CAS  PubMed  Google Scholar 

  • Pommier Y, Redon C, Rao VA, Seiler JA, Sordet O, Takemura H, Antony S, Meng L, Liao Z, Kohlhagen G, Zhang H, Kohn KW (2003) Repair of and checkpoint response to topoisomerase I-mediated DNA damage. Mutat Res 532:173–203

    Google Scholar 

  • Pouliot JJ, Yao KC, Robertson CA, Nash HA (1999) Yeast gene for a Tyr–DNA phosphodiesterase that repairs topoisomerase I complexes. Science 286:552–555

    Google Scholar 

  • Pouliot JJ, Robertson CA, Nash HA (2001) Pathways for repair of topoisomerase I covalent complexes in Saccharomyces cerevisiae. Genes Cells 6:677–687

    Google Scholar 

  • Rallabhandi P, Hashimoto K, Mo YY, Beck WT, Moitra PK, D’Arpa P (2002) Sumoylation of topoisomerase I is involved in its partitioning between nucleoli and nucleoplasm and its clearing from nucleoli in response to camptothecin. J Biol Chem 277:40020–40026

    Google Scholar 

  • Redinbo MR, Stewart L, Kuhn P, Champoux JJ, Hol WG (1998) Crystal structures of human topoisomerase I in covalent and noncovalent complexes with DNA. Science 279:1504–1513

    Google Scholar 

  • Redinbo MR, Stewart L, Champoux JJ, Hol WG (1999) Structural flexibility in human topoisomerase I revealed in multiple non-isomorphous crystal structures. J Mol Biol 292:685–696

    Google Scholar 

  • Redinbo MR, Champoux JJ, Hol WG (2000) Novel insights into catalytic mechanism from a crystal structure of human topoisomerase I in complex with DNA. Biochemistry 39:6832–6840

    Google Scholar 

  • Rossi F, Labourier E, Forne T, Divita G, Derancourt J, Riou JF, Antoine E, Cathala G, Brunel C, Tazi J (1996) Specific phosphorylation of SR proteins by mammalian DNA topoisomerase I. Nature 381:80–82

    Google Scholar 

  • Rubbi CP, Milner J (2003) Disruption of the nucleolus mediates stabilization of p53 in response to DNA damage and other stresses. EMBO J 22:6068–6077

    Google Scholar 

  • Schwarzacher HG, Wachtler F (1993) The nucleolus. Anat Embryol (Berl) 188:515–536

    Google Scholar 

  • Seeler JS, Dejean A (2003) Nuclear and unclear functions of SUMO. Nat Rev Mol Cell Biol 4:690–699

    Article  CAS  PubMed  Google Scholar 

  • Sokhansanj BA, Wilson DM III (2004) Oxidative DNA damage background estimated by a system model of base excision repair. Free Radic Biol Med 37:422–427

    Google Scholar 

  • Sordet O, Khan QA, Plo I, Pourquier P, Urasaki Y, Yoshida A, Antony S, Kohlhagen G, Solary E, Saparbaev M, Laval J, Pommier Y (2004) Apoptotic topoisomerase I–DNA complexes induced by staurosporine-mediated oxygen radicals. J Biol Chem 279:50499–50504

    Google Scholar 

  • Staker BL, Hjerrild K, Feese MD, Behnke CA, Burgin AB Jr, Stewart L (2002) The mechanism of topoisomerase I poisoning by a camptothecin analog. Proc Natl Acad Sci U S A 99:15387–15392

    Google Scholar 

  • Stewart L, Ireton GC, Champoux JJ (1997) Reconstitution of human topoisomerase I by fragment complementation. J Mol Biol 269:355–372

    Google Scholar 

  • Stewart L, Redinbo MR, Qiu X, Hol WG, Champoux JJ (1998) A model for the mechanism of human topoisomerase I. Science 279:1534–1541

    Google Scholar 

  • Stewart L, Ireton GC, Champoux JJ (1999) A functional linker in human topoisomerase I is required for maximum sensitivity to camptothecin in a DNA relaxation assay. J Biol Chem 274:32950–32960

    Google Scholar 

  • Straub T, Grue P, Uhse A, Lisby M, Knudsen BR, Tange TO, Westergaard O, Boege F (1998) The RNA-splicing factor PSF/p54 controls DNA-topoisomerase I activity by a direct interaction. J Biol Chem 273:26261–26264

    Google Scholar 

  • Strumberg D, Pilon AA, Smith M, Hickey R, Malkas L, Pommier Y (2000) Conversion of topoisomerase I cleavage complexes on the leading strand of ribosomal DNA into 5′-phosphorylated DNA double-strand breaks by replication runoff. Mol Cell Biol 20:3977–3987

    Google Scholar 

  • Tanizawa A, Kohn KW, Pommier Y (1993) Induction of cleavage in topoisomerase I c-DNA by topoisomerase I enzymes from calf thymus and wheat germ in the presence and absence of camptothecin. Nucleic Acids Res 21:5157–5166

    Google Scholar 

  • Vance JR, Wilson TE (2002) Yeast Tdp1 and Rad1–Rad10 function as redundant pathways for repairing Top1 replicative damage. Proc Natl Acad Sci U S A 99:13669–13674

    Google Scholar 

  • Vousden KH, Lu X (2002) Live or let die: the cell’s response to p53. Nat Rev Cancer 2:594–604

    Article  CAS  PubMed  Google Scholar 

  • Wang JC (1985) DNA topoisomerases. Annu Rev Biochem 54:665–697

    Google Scholar 

  • Wang JC (1996) DNA topoisomerases. Annu Rev Biochem 65:635–692

    Google Scholar 

  • Wang JC (2002) Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol 3:430–440

    Google Scholar 

  • Woo MH, Losasso C, Guo H, Pattarello L, Benedetti P, Bjornsti MA (2003) Locking the DNA topoisomerase I protein clamp inhibits DNA rotation and induces cell lethality. Proc Natl Acad Sci U S A 100:13767–13772

    Google Scholar 

  • Wu Y, Hickey R, Lawlor K, Wills P, Yu F, Ozer H, Starr R, Quan JY, Lee M, Malkas L (1994) A 17S multiprotein form of murine cell DNA polymerase mediates polyomavirus DNA replication in vitro. J Cell Biochem 54:32–46

    Google Scholar 

  • Yang SW, Burgin AB Jr, Huizenga BN, Robertson CA, Yao KC, Nash HA (1996) A eukaryotic enzyme that can disjoin dead-end covalent complexes between DNA and type I topoisomerases. Proc Natl Acad Sci U S A 93:11534–11539

    Google Scholar 

  • Zechiedrich EL, Osheroff N (1990) Eukaryotic topoisomerases recognize nucleic acid topology by preferentially interacting with DNA crossovers. EMBO J 9:4555–4562

    Google Scholar 

  • Zhang H, Wang JC, Liu LF (1988) Involvement of DNA topoisomerase I in transcription of human ribosomal RNA genes. Proc Natl Acad Sci U S A 85:1060–1064

    Google Scholar 

  • Zhang CX, Chen AD, Gettel NJ, Hsieh TS (2000) Essential functions of DNA topoisomerase I in Drosophila melanogaster. Dev Biol 222:27–40

    Google Scholar 

  • Zhang H, Barcelo JM, Lee B, Kohlhagen G, Zimonjic DB, Popescu NC, Pommier Y (2001) Human mitochondrial topoisomerase I. Proc Natl Acad Sci U S A 98:10608–10613

    Google Scholar 

  • Zhang H, Meng LH, Zimonjic DB, Popescu NC, Pommier Y (2004) Thirteen-exon-motif signature for vertebrate nuclear and mitochondrial type IB topoisomerases. Nucleic Acids Res 32:2087–2092

    Google Scholar 

Download references

Acknowledgements

We thank Sharon Schultz and Heidrun Interthal for insightful comments during the preparation of the manuscript. This work was supported by grants GM60330 and GM49156 from the National Institutes of Health.

Author information

Authors and Affiliations

  1. Department of Microbiology, School of Medicine, University of Washington, P.O. Box 357242, 1959 N.E. Pacific St., Seattle, WA, 98195-7242, USA

    John B. Leppard & James J. Champoux

Authors
  1. John B. Leppard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James J. Champoux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James J. Champoux.

Additional information

Communicated by E. A. Nigg

Rights and permissions

Reprints and permissions

About this article

Cite this article

Leppard, J.B., Champoux, J.J. Human DNA topoisomerase I: relaxation, roles, and damage control. Chromosoma 114, 75–85 (2005). https://doi.org/10.1007/s00412-005-0345-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00412-005-0345-5

Keywords

Search

Navigation