Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1998-09-09
2001-08-28
Yucel, Remy (Department: 1636)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C435S320100, C435S325000, C435S252300, C435S252330
Reexamination Certificate
active
06281347
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to human origin of replication complex genes and their uses.
BACKGROUND OF THE INVENTION
DNA replication in eukaryotic cells is tightly controlled and coordinated with other events during the cell cycle and cell proliferation. Studies carried out with the budding yeast,
Saccharomyces cerevisiae
, led to the identification of an origin recognition complex (“ORC”) (Bell, S. P., et al., “ATP-dependent Recognition of Eukaryotic Origins of DNA Replication by a Multiprotein Complex,”
Nature,
357:128-34 (1992)). ORC consists of six polypeptides (i.e. ORC1 to ORC6) and plays an essential role in the initiation of chromosome DNA replication and transcriptional silencing in the budding yeast (Bell, S. P., et al., “Yeast Origin Recognition Complex Functions in Transcription Silencing and DNA Replication,”
Science,
262:1844-49 (1993); Bell, S. P., et al., “ATP-dependent Recognition of Eukaryotic Origins of DNA Replication by a Multiprotein Complex,”
Nature,
357:128-34 (1992); Micklem, G., et al., “Yeast Origin Recognition Complex is Involved in DNA Replication and Transcriptional Silencing,”
Nature,
366:87-89 (1993)). This six-protein complex binds to several well defined autonomously replicating sequences that serve as the chromosomal replication origins in an ATP-dependent manner (Bell, S. P., et al., “ATP-dependent Recognition of Eukaryotic Origins of DNA Replication by a Multiprotein Complex,”
Nature,
357:128-34 (1992)). The genes for all six ORC subunits have been isolated and deletion of any one of these genes results in lethality (Bell, S. P., et al., “Yeast Origin Recognition Complex Functions in Transcription Silencing and DNA Replication,”
Science,
262:1844-49 (1993); Bell, S. P., et al., “The Multidomain Structure of Orc 1 p Reveals Similarity to Regulators of DNA Replication and Transcriptional Silencing,”
Cell,
83:563-68 (1995); Foss, et al., “Origin Recognition Complex (ORC) in Transcriptional Silencing and DNA Replication in
S. cerevisiae,” Science,
262:1838-44 (1993); Li, J. J., et al., “Isolation of ORC6, a Component of the Yeast Origin Recognition Complex by a One-Hybrid System,”
Science,
262:1870-74 (1993); Loo, S., et al., “The Origin Recognition Complex in Silencing, Cell Cycle Progression, and DNA Replication,”
Mol. Biol. Cell,
6:741-56 (1995); Micklem, G., et al., “Yeast Origin Recognition Complex is Involved in DNA Replication and Transcriptional Silencing,”
Nature,
366:87-89 (1993)). The regulation of initiation of metazoan chromosomal DNA replication is poorly understood, because chromosomal origins have not been localized to specific DNA sequences. Recently, cDNA clones encoding proteins homologous to the
S. cerevisiae
ORC have been isolated from
Schizosaccharomyces pombe, Xenopus laevis
, and human for both ORC1 and ORC2, from
kluyveromyces lactis
for ORC1, and from
Caenorhabditis elegans, Arabidopsis thaliana
and mouse for ORC2 (Carpenter, P. B., et al., “Role for a Xenopus Orc2-related Protein in Controlling DNA Replication,”
Nature,
379:357-60 (1996); Gavin, K. A., et al., “Conserved Initiator Proteins in Eukaryotes,”
Science,
270:1667-71 (1995); Leatherwood, J., et al., “Interaction of Cdc2 and Cdc18 with a Fission Yeast ORC2-like Protein,”
Nature,
379:360-63 (1996); Muzi-Falconi, M., et al., “Orp1, a Member of the Cdc18/Cdc6 Family of S-phase Regulators, is Homologous to a Component of the Origin Recognition Complex,”
Proc. Natl. Acad. Sci. USA,
92:12475-79 (1995); Rowles, A., et al., “Interaction Between the Origin Recognition Complex and the Replication Licensing System in Xenopus,”
Cell,
87:287-96 (1996); Takahara, K., et al., “Mouse and Human Homologues of the Yeast Origin of Replication Recognition Complex Subunit ORC2 and Chromosomal Localization of the Cognate Human Gene ORC2L,”
Genomics,
31:119-22 (1996)). The Orc2 and Orc5 homologues have also been cloned from
Drosophila melanogaster
(Gossen, M., et al., “A Drosophila Homolog of the Yeast Origin Recognition Complex,”
Science,
270:1674-77 (1995)). A multisubunit protein complex made up of subunits homologous to the
S. cerevisiae
ORC genes has been purified from Drosophila and Xenopus (Gossen, M., et al., “A Drosophila Homolog of the Yeast Origin Recognition Complex,”
Science,
270:1674-77 (1995); Rowles, A., et al., “Interaction Between the Origin Recognition Complex and the Replication Licensing System in Xenopus,”
Cell,
87:287-96 (1996)).
Although origin of recognition complex subunits have been isolated and sequenced in some species, including human (i.e. ORC1 and ORC2), the need remains for such work to be carried out for other subunits. The present invention is directed to fulfilling this objective.
SUMMARY OF THE INVENTION
The present invention relates to isolated DNA molecules encoding human origin of recognition complex subunit 4 and human origin of recognition complex subunit 5. Also disclosed is the isolated human origin of recognition complex subunit 4 protein or polypeptide and the human origin of recognition complex subunit 5 protein or polypeptide.
Another aspect of the present invention relates to a method of identifying compounds for a pharmacological agent useful in the diagnosis or treatment of disease associated with cell growth. This method involves forming a mixture comprising (1) either a human origin of recognition complex subunit 4 protein or polypeptide or a human origin of recognition complex subunit 5 protein or polypeptide, (2) an intracellular protein binding target capable of specifically binding to human origin of recognition complex 4 protein or polypeptide or a human origin of recognition complex subunit 5 protein or polypeptide, and (3) a candidate pharmacological agent. The mixture is then incubated under conditions effective, but for the candidate pharmacological agent, for the human origin of recognition complex subunit 4 protein or polypeptide or the human origin of recognition complex subunit 5 protein or polypeptide to bind to the binding target. The presence or absence of specific binding of the human origin of recognition complex subunit 4 protein or polypeptide or the human origin of recognition complex subunit 5 protein or polypeptide to the binding target is then detected. The absence of selective binding indicates that the candidate pharmacological agent is a lead compound that disrupts cellular function of the human origin of recognition complex subunit 4 protein or polypeptide or the human origin of recognition complex subunit 5 protein or polypeptide and inhibits cell growth.
REFERENCES:
patent: 5589341 (1996-12-01), Stillman et al.
patent: 5614618 (1997-03-01), Stillman et al.
patent: WO 95/16694 (0000-01-01), None
Quintana et al., “Identification of HsORC4, a Member of the Human Origin of Replication Recognition Complex,”The Journal of Biological Chemistry, 272(45):28247-28251 (1997).
Ishiai et al., “Isolation of Human and Fission Yeast Homologues of the Budding Yeast Origin Recognition Complex Subunit ORC5: Human Homologue (ORC5L) Maps to 7q22,”Genomics, 46:294-298 (1997).
Bell et al., “ATP-dependent Recognition of Eukaryotic Origins of DNA Replication by a Multiprotein Complex,”Nature, 357:128-134 (1992).
Muzi-Falconi et al., “Orp1, A Member of the Cdc18/Cdc6 Family of S-phase Regulators, is Homologous to a Component of the Origin Recognition Complex,”Proc. Natl. Acad. Sci. USA, 92:12475-12479 (1995).
Gavin et al., “Conserved Initiator proteins in Eukaryotes,”Science, 270:1667-71 (1995).
Donovan et al., “Replication Origins of Eukaryotes,”Curr. Opin. Genet. Dev., 6(2):203-7 (1996) (abstract).
Loo et al., “Silencing and Heritable Domains of Gene Expression,”Ann. Rev. Cell. Dev. Biol., 11:519-48 (1995) (abstract).
Hardy, “Characterization of an Essential Orc2p-Associated Factor That Plays a Role in DNA Replication,”Mol. Cell Biol., 16(4):1832-41 (1996).
Bell et al., “The Multidomain Structure Orc1p Reveals Similarity to Regulators of DNA Replication and Transcriptional Silencing,”Cell, 83:563-568 (1995).
Loo et al., “The Origina Recognition
Bruck Irena
Dean Frank
O'Donnell Michael
Nixon & Peabody LLP
Yucel Remy
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