The new study, published in the September issue of Nature Structural & Molecular Biology, describes how the protein Upf1 helps cells synchronize the synthesis of both DNA and histones, the group of proteins 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 usually lethal for the cell, said Dr. William Marzluff, lead author of the study and Kenan distinguished professor of biochemistry and biophysics at UNC's School of Medicine.
"This is one of the safeguards that our cells have evolved and it is a part of the normal progression through cell division – all growing cells have to use this all of the time," he said.
The paper by Marzluff and UNC biology graduate student Handan Kaygun shows how Upf1 prevents the cell from making any unwanted histone proteins during the intervals between DNA syntheses.
"Every time a cell divides, it has to replicate both DNA and histone proteins and then package the two together into chromosomes," Marzluff said. "That way, each of the two cells resulting from division has 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 then acts as a guide for building a histone protein. Because the RNA relays a message, in this case the blueprint for a histone protein, it is referred to as messenger RNA, or mRNA.
In 1987, Marzluff and his laboratory identified a portion of the histone messenger RNA that the cell needs to coordinate histone synthesis with DNA synthesis.
The new paper shows how Upf1 attaches to histone messenger RNA at the completion of DNA replication. As a result, histone mRNA is degraded, thus halting further histone production.
"For about 10 years, we have known how the cell recognizes abnormal messenger RNAs and gets rid of them," Marzluff said. "We found that the key protein in that system, Upf1, is the same protein that triggers the degradation of histone messenger RNA, a normal cellular message. So this RNA removal process that was largely thought to be reserved for quality control is also critical for normal histone messenger RNAs."
Histone messenger RNAs are present at much higher levels in tumors than in other cells, Marzluff added. "In fact, assays for histone messages have been used as a diagnostic in tumors. That's why understanding histone regulation is clearly important for understanding cell growth regulation, including tumor growth."
Marzluff and Kaygun also showed that Upf1 plays a role in ridding the cell of histone messenger RNA when the process of DNA synthesis is disturbed.
"When DNA synthesis stalls because its replication is blocked by ultraviolet light or toxic chemicals, for example, the cell pauses to fix things," said Marzluff.
But without Upf1, or another protein called ATR that becomes activated when DNA synthesis is paused, histone messenger RNA is not destroyed, thus allowing histone proteins to accumulate at dangerously high levels.
"This is the first time that we've been able to link DNA damage at the site of replication to the degradation of histone messenger RNA," Marzluff said.
The study was supported by a grant from the National Institutes of Health.
Note: Contact Marzluff at (919) 962-8920 or william_marzluff@med.unc.edu
School of Medicine contact: Les Lang, (919) 843-9687 or llang@med.unc.edu
Journal
Nature Structural & Molecular Biology