DNA Replication Initiator Proteins and Genetic Instability: Creating a Mouse Model for Prostate Cancer
Abstract
Hyperploidy is a well-known pathological hallmark of cancer cells including prostate cancer. The mechanisms underlying this form of genomic instability are essentially unknown. We have identified a pathway in fission yeast critical for maintaining DNA replication control. Two genes in the pathway, POPl and POP2, encode WD4C domain proteins that heterodimerize to hind to regulatory proteins and promote their ubiquitin-dependent proteolysis. The targets of this proteolytic destruction machinery include regulators of cyclin-dependent kinases, cyclins, Cdk inhibitors, and the replication initiator protein, Cdcl8. Mutations in Popl or Pop2 cause yeast to accumulate these regulators and to prominently overreplicate their genomes (>8N) . Accordingly, the POP genes behave as "rereplication suppressors" in yeast. We have identified human and mouse homologs of the POP genes which we have called hPOPl and mPOPl. These genes encode proteins that are overall 21% identical and 55% similar to yeast equivalents, hut have higher degrees of homology in some domains. We have begun to test whether these proteins serve a similar role in mammalian cells. Using radiation hybrid mapping and FISH, we have mapped the human POPl to a region that has been suggested to contain a potential tumor suppressor for urogenital cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2000
- Accession Number
- ADA391522
Entities
People
- Peter K Jackson
Organizations
- Stanford University