DNA molecules encoding single strand gap response proteins...

Details DNA molecules encoding single strand gap response proteins... DNA molecules encoding single strand gap response proteins...

1999-04-16

2002-09-24

Ketter, James (Department: 1636)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C435S071100, C435S069100, C435S471000, C435S455000, C435S320100, C435S252300, C435S325000, C530S350000, C514S04400A, C424S093100

Reexamination Certificate

active

06455681

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to isolated DNA molecules encoding single strand gap response proteins involved in activation of a DNA repair/cell cycle checkpoint pathway, as well as diagnostic and therapeutic uses of the DNA molecules, their expressed proteins or polypeptides, and antibodies raised against the proteins or polypeptides.
BACKGROUND OF THE INVENTION
The progression of a eukaryotic cell through the stages of the cell cycle can be arrested if the events of the previous stage of the cell cycle, such as DNA replication, have not been completed or, in addition, if the DNA has sustained some type of damage. The controls on cell cycle progression are termed checkpoints (Hartwell, L., et al., “Checkpoints: Controls That Ensure the Order of Cell Cycle Events,”
Science
, 246:629-34 (1989)), and they can be used to detect whether the processes of the individual stages of the cell cycle have been completed and whether the DNA is intact or in need of repair. Genes whose expressed products are involved in cell cycle delay or DNA repair are broadly defined as checkpoint control genes. Cells that are mutated in one of the cell cycle checkpoint control genes, however, are able to proceed from one stage of the cell cycle to the next even if the cellular processes of that stage are incomplete or in the presence of DNA damage. The G2 phase of the cell cycle lies between S phase, in which DNA replication takes place, and M phase, when mitosis occurs. Thus, the G2 checkpoint is critical for ensuring that mitosis does not occur until all the necessary steps of DNA replication, DNA repair, and chromosome duplication are complete.
Many checkpoint-deficient mutants have been identified in the budding yeast
Saccharomyces cerevisiae
and in the fission yeast
Schizosaccharomyces pombe.
Genes have been isolated that link mitosis to the completion of DNA replication. Enoch, T., et al., “Mutation of Fission Yeast Cell Cycle Control Genes Abolishes Dependence of Mitosis on DNA Replication,”
Cell
, 60:665-73 (1990); Enoch, T., et al., “Fission Yeast Genes Involved in Coupling Mitosis to Completion of DNA Replication,”
Genes Dev
., 6:2035-46 (1992); McFarlane, R. J., et al., “Characterization of the
Schizosaccharomyes pombe
rad4/cut5 Mutant Phenotypes: Dissection of DNA Replication and G2 Checkpoint Control Function,”
Mol. Gen. Genet
., 255:332-40 (1997). In addition, many genes that function in DNA repair have been identified as G2 checkpoint control genes. Nasim, A., et al., “Genetic Control of Radiation Sensitivity in
Schizosaccharomyces pombe,” Genetics
, 79:573-82 (1975); Al-Khodairy, F., et al., “DNA Repair Mutants Defining G2 Checkpoint Pathways in
Schizosaccharomyces pombe,” EMBO J
., 11:1343-50 (1992); Al-Khodairy, F., et al., “Identification and Characterization of New Elements Involved in Checkpoint and Feedback Controls in Fission Yeast,”
Mol. Biol. Cell
, 5:147-60 (1994). Several examples include
Saccharomyces cerevisiae
RAD9 (Weinert, T. A., et al., “Characterization of RAD9 of
Saccharomyces cerevisiae
and Evidence that Its Function Acts Post-Translationally in Cell Cycle Arrest after DNA Damage,”
Mol. Cell. Biol
., 10:6554-64 (1990)),
Saccharomyces cerevisiae
MEC3 (Weinert, T. A., et al., “Mitotic Checkpoint Genes in Budding Yeast and the Dependence of Mitosis on DNA Replication and Repair,”
Genes
&
Dev
., 8:652-65 (1994)),
Schizosaccharomyces pombe
rad1 (Rowley, R., et al., “Checkpoint Controls in
Schizosaccharomyces pombe
: rad1
, ” EMBO J
., 11:1335-42 (1992)),
Schizosaccharomyces pombe
rad3 (Jimenez, G., et al., “The rad3
+
Gene of
Schizosaccharomyces pombe
is Involved in Multiple Checkpoint Functions and in DNA Repair,”
Proc. Natl. Acad. Sci. USA
, 89:4952-56 (1992); Bentley, N. J., et al., “The
Schizosaccharomyces pombe
rad3 Checkpoint Gene,”
EMBO J
., 15:6641-51 (1996)),
Schizosaccharomyces pombe
rad17 (Griffiths, D. J. F., et al., “Fission Yeast rad17: a Homolog of Budding Yeast RAD24 That Shares Regions of Sequence Similarity with DNA Polymerase Accessory Proteins,”
EMBO J
., 14:5812-23 (1995)),
Schizosaccharomyces pombe
hus1 (Kostrub, C. F., et al., “Molecular Analysis of hus1
+
, a Fission Yeast Gene Required for S-M and DNA Damage Checkpoints,”
Mol. Gen. Genet
., 254:389-99 (1997)), and the fungus
Ustilago maydis
REC1 (One1, K., et al., “The REC1 Gene of
Ustilago maydis
. Which Encodes a 3′-5′ Exonuclease, Couples DNA Repair and Completion of DNA Synthesis to a Mitotic Checkpoint,”
Genetics
, 143:165-74 (1996)). A number of reviews summarize this work. Sheldrick, K. S., et al., “Feedback Controls and G2 Checkpoints: Fission Yeast as a Model System,”
BioEssays
, 15:775-82 (1993); Lydall, D., et al., “From DNA Damage to Cell Cycle Arrest and Suicide: A Budding Yeast Perspective,”
Curr. Opin. Genet. Dir
. 6:4-11 (1996); Stewart, E., et al., “S-phase and DNA-damage Checkpoints: a Tale of Two Yeasts,”
Curr. Opin. Cell Biol
., 8:781-87 (1996); Carr, A. M., “Control of Cell Cycle Arrest by the Mec1
sc
/Rad3
sp
DNA Structure Checkpoint Pathway,”
Curr. Opin. Genet. Dev
., 7:93-98 (1997). Some of the
Saccharomyces cerevisiae
and
Schizosaccharomyces pombe
genes involved in the G2 cell cycle checkpoint are summarized in FIG.
1
.
A human homolog of the
Schizosaccharomyces pombe
rad9 checkpoint control gene was described recently. Lieberman, H. B., et al., “A Human Homolog of the
Schizosaccharomyces pombe
rad9
+
Checkpoint Control Gene,”
Proc. Natl. Acad. Sci. USA
, 93:13890-95 (1996). The mapping of a human homolog to
Schizosaccharomyces pombe
rad1 was reported. Parker, A., et al., “Identification of a Putative Human Homolog of the
Schizosaccharomyces pombe
rad1 Checkpoint Gene”,
Eukayrotic DNA Replication
, p. 179, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1997). Interestingly, referring to
FIG. 1
, two
Saccharomyces cerevisiae
genes, MEC3 and RAD9, do not appear to have
Schizosaccharomyces pombe
or human homologs, while
Saccharomyces cerevisiae
does not carry homologs for
Schizosaccharomyces pombe
hus1 or rad9. The checkpoint control systems of
Saccharomyces cerevisiae
and
Schizosaccharomyces pombe
have some gene homologs in common; however, they appear to have diverged significantly, perhaps because cell division is so different in these organisms.
Saccharomyces cerevisiae
divides by budding, while
Schizosaccharomyces pombe
divides by fission. The mitosis and cell division of
Schizosaccharomyces pombe
is much more similar to that of human cells than the mitosis and cell division of
Saccharomyces cerevisiae. Schizosaccharomyces pombe
has a distinct G2 phase of the cell cycle and, in addition, the chromosomes undergo condensation during mitosis. Russell, P., et al., “
Schizosaccharomyces pombe
and
Saccharomyces cerevisiae
: A Look at Yeasts Divided,”
Cell
, 45:781-82 (1986). This may be why the human genes of the G2 cell cycle checkpoint pathway correspond so much more closely to the genes of
Schizosaccharomyces pombe
than to the genes of
Saccharomyces cerevisiae.
The occurrence of mutations in checkpoint control genes of higher eukaryotes can lead to cancer. Hartwell, L., “Defects in a Cell Cycle Checkpoint may be Responsible for the Genomic Instability of Cancer Cells,”
Cell
, 71:543-46 (1992); Hartwell, L., et al., “Cell Cycle Control and Cancer,”
Science
, 266:1821-28 (1994); Kastan, M. B., et al., “Participation of p53 Protein in the Cellular Response to DNA Damage,”
Cancer Res
., 51:6304-11 (1991); Kuerbitz, S. J., et al., “Wild-Type p53 is a Cell Cycle Checkpoint Determinant Following Irradiation,”
Proc. Natl. Acad. Sci. USA
, 89:7491-95 (1992). Genes which, when mutated, allow increased rates of tumor formation are termed tumor suppressors. Many tumor suppressors have cell cycle checkpoint function, and loss-of-function mutations in these genes causes runaway cell proliferation, leading to tumor formation. Collins, K., et al., “The Cell Cycle and Cancer,”
Proc. Natl. Acad. Sci. USA
, 94:2776-78 (1997). For e

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