Scientists Discover Protein Responsible for DNA Replication

Scientists are discovering the proteins that control the way human DNAcopies itself, a breakthrough that may lead to new treatments for canceror heart disease.

Dr. R. Sanders Williams, professor of internal medicine and chief ofcardiology at UT Southwestern Medical Center at Dallas, has identifieda protein thought to function in the initiation of DNA replication. Thediscovery was made during his year-long sabbatical at Cold Spring HarborLaboratory in New York where he conducted research with Dr. Bruce Stillman.

The discovery of the gene, termed p62cdcd6, is reported in the January7th issue of The Proceedings of the Academy of Sciences.

"When cells divide, each of the three billion nucleotides in theentire human genome must be copied once, and only once, and this processmust be completed in just a few hours," Williams said. "If theprocess goes awry by producing too many or too few copies of a segmentof the genome, serious problems can result."

Williams said Stillman has been a major leader in the field of cell-cyclecontrol, using yeast models to learn how DNA replication is triggered.

"A yeast protein called cdc6p proves to be a critical regulatorycomponent that is involved in both replication licensing--preparing thechromosome to be ready to replicate--and in the process by which the cellreplicates DNA precisely once in each cell cycle," Williams said.

Compared to yeasts, very little is known about what triggers DNA replicationin higher organisms, including humans. The discovery of so-called "initiator"proteins like p62cdcd6 in human cells opens the door to greater understandingof mechanisms of tumor development and the events by which certain cells,like those of the heart, lose the capacity to replicate DNA.

Authors Williams, Stillman, and Dr. Ralph Shohet, assistant professorof internal medicine at UT Southwestern, speculate that the human DNA-replicatorprotein will serve a similar function as the yeast DNA-replicator counterpart.

"It appears the basic machinery of DNA replication and origin firingis conserved across all of life," Williams said.

Role of Protein in Human Cancers Still to Be Elucidated

The discovery is pertinent to cancer because mutations in yeast cdc6pcause abnormalities very similar to human malignancies. Scientists arenot yet sure of the role of p62cdcd6 in human tumors, but it could becomea novel target for therapies to stop cells from replicating DNA.

Knowledge about this protein also may be useful in heart disease.

"There are some cells that don't replicate their DNA when we wantthem to--like heart cells after a heart attack," said Williams, whois director of the Frank M. Rybum Jr. Cardiac Center at UT Southwesternand holder of the James T. Willerson, MD, Distinguished Chair in CardiovascularDiseases.

The work was communicated to the journal by Dr. James D. Watson of ColdSpring Harbor Laboratory and was supported by funds from the National Institutesof Health.