Study Identifies Protein's Role In Cell Division; May Offer New Knowledge Into Tumor Growth

The new study, published in the September issue of Nature Structural& Molecular Biology, describes how the protein Upf1 helps cellssynchronize the synthesis of both DNA and histones, the group ofproteins that organize DNA within a cell's nucleus.

The findings may offer new knowledge into the molecular mechanisms involved in tumor growth.

An imbalance in the production of DNA and histones is usuallylethal for the cell, said Dr. William Marzluff, lead author of thestudy and Kenan distinguished professor of biochemistry and biophysicsat UNC's School of Medicine.

"This is one of the safeguards that our cells have evolved andit is a part of the normal progression through cell division -- allgrowing cells have to use this all of the time," he said.

The paper by Marzluff and UNC biology graduate student HandanKaygun shows how Upf1 prevents the cell from making any unwantedhistone proteins during the intervals between DNA syntheses.

"Every time a cell divides, it has to replicate both DNA andhistone proteins and then package the two together into chromosomes,"Marzluff said. "That way, each of the two cells resulting from divisionhas one complete set of genes."

In humans, the 23 chromosomes that house roughly 35,000 genes are made up of both DNA and histone proteins.

Histone proteins are made in the same way as any other proteins.The DNA from a histone gene is first transcribed into RNA, which thenacts as a guide for building a histone protein. Because the RNA relaysa message, in this case the blueprint for a histone protein, it isreferred to as messenger RNA, or mRNA.

In 1987, Marzluff and his laboratory identified a portion ofthe histone messenger RNA that the cell needs to coordinate histonesynthesis with DNA synthesis.

The new paper shows how Upf1 attaches to histone messenger RNAat the completion of DNA replication. As a result, histone mRNA isdegraded, thus halting further histone production.

"For about 10 years, we have known how the cell recognizesabnormal messenger RNAs and gets rid of them," Marzluff said. "We foundthat the key protein in that system, Upf1, is the same protein thattriggers the degradation of histone messenger RNA, a normal cellularmessage. So this RNA removal process that was largely thought to bereserved for quality control is also critical for normal histonemessenger RNAs."

Histone messenger RNAs are present at much higher levels intumors than in other cells, Marzluff added. "In fact, assays forhistone messages have been used as a diagnostic in tumors. That's whyunderstanding histone regulation is clearly important for understandingcell growth regulation, including tumor growth."

Marzluff and Kaygun also showed that Upf1 plays a role inridding the cell of histone messenger RNA when the process of DNAsynthesis is disturbed.

"When DNA synthesis stalls because its replication is blockedby ultraviolet light or toxic chemicals, for example, the cell pausesto fix things," said Marzluff.

But without Upf1, or another protein called ATR that becomesactivated when DNA synthesis is paused, histone messenger RNA is notdestroyed, thus allowing histone proteins to accumulate at dangerouslyhigh levels.

"This is the first time that we've been able to link DNA damageat the site of replication to the degradation of histone messengerRNA," Marzluff said.

The study was supported by a grant from the National Institutes of Health.