Featured Research

from universities, journals, and other organizations

Scientists uncover role of protein critical for activating DNA replication

Date:
January 11, 2010
Source:
Cold Spring Harbor Laboratory
Summary:
Scientists have discovered how a protein long known to be an essential activator of DNA replication actually triggers this process in cells. The protein, called DDK (for Ddf4-dependent protein kinase), is one of two cell-cycle-regulated protein kinases that facilitate coordination with other processes during cell division. DDK is now shown to block the inhibitory activity of a domain within the DNA unwinding enzyme Mcm4, thereby promoting DNA replication.

Scientists at Cold Spring Harbor Laboratory (CSHL) have discovered how a protein long known to be an essential activator of DNA replication actually triggers this process in cells.

The protein, called DDK (for Ddf4-dependent protein kinase), is an enzyme that attaches phosphate molecules to other proteins to modify their activity. The CSHL team has found that DDK performs this operation, called phosphorylation, on a protein called Mcm4, specifically within a domain that acts as a built-in brake to prevent the DNA double helix from being unwound. The phosphorylation by DDK releases this brake, thus initiating the replication of unwound DNA strands.

"As DDK is often deregulated in human cancers, this new understanding of its role in DNA replication may help shape the development of new cancer therapies," explains CSHL President Bruce Stillman, Ph.D., who co-authored the study with colleague Yi-Jun Sheu, Ph.D. "Indeed recent studies have identified DDK inhibitors and they are now in clinical trials." The report was published in Nature on 7th January.

In multicellular organisms, the duplication of the DNA in chromosomes starts at multiple sites, called origins, within the genome. For the genome to retain its integrity each time a cell divides, it's crucial that each origin "fires," or becomes active, just once and only during a timeframe in the cell cycle known as the S-phase.

A large number of proteins cooperate and interact with military precision to ensure this "once-only" condition. First, a group of proteins cluster at each origin site to form a pre-replication complex or pre-RC. The phosphorylation of some pre-RC components by DDK in turn recruits other proteins to these pre-RCs, converting them into pre-initiation complexes, or pre-ICs.

Over the last 15 years, Dr. Stillman's group has systematically uncovered many of the pre-RC and pre-IC proteins, and meticulously catalogued when and where each protein interacts with its collaborators. Having found out previously that DDK targets a multi-subunit protein complex called MCM, they've now narrowed down DDK's binding site to a domain within one of the subunits, Mcm4, where it phosphorylates a series of amino acids -- protein building blocks -- that otherwise inhibit Mcm4 from functioning.

The discovery of this self-inhibitory activity within Mcm4 and the finding that DDK is required to overcome it was a surprise, according to the authors. They propose that such complexity might have evolved in response to the importance of precision and accuracy of DNA replication.

"Although this is the only essential role for DDK under normal conditions, we have found that DDK takes on another task when the cell suffers DNA damage," says Dr. Stillman. In this hazardous situation, he and his colleague found, DDK activates an S-phase checkpoint mechanism that halts the DNA copying process and initiates DNA repair.

"This discovery of these distinct functions of DDK represents a key piece of the puzzle of how the initiation of DNA replication is coordinated and controlled by kinase proteins," says Dr. Stillman.

This research was supported by a grant from the U.S. National Institute of General Medical Sciences.


Story Source:

The above story is based on materials provided by Cold Spring Harbor Laboratory. Note: Materials may be edited for content and length.


Journal Reference:

  1. Yi-Jun Sheu and Bruce Stillman. The Cdc7-Dbf4 kinase promotes S phase progression by alleviating an inhibitory activity in Mcm4. Nature, January 7, 2010 DOI: 10.1038/nature08647

Cite This Page:

Cold Spring Harbor Laboratory. "Scientists uncover role of protein critical for activating DNA replication." ScienceDaily. ScienceDaily, 11 January 2010. <www.sciencedaily.com/releases/2010/01/100107114426.htm>.
Cold Spring Harbor Laboratory. (2010, January 11). Scientists uncover role of protein critical for activating DNA replication. ScienceDaily. Retrieved August 20, 2014 from www.sciencedaily.com/releases/2010/01/100107114426.htm
Cold Spring Harbor Laboratory. "Scientists uncover role of protein critical for activating DNA replication." ScienceDaily. www.sciencedaily.com/releases/2010/01/100107114426.htm (accessed August 20, 2014).

Share This




More Health & Medicine News

Wednesday, August 20, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Ebola-Hit Sierra Leone's Freetown a City on Edge

Ebola-Hit Sierra Leone's Freetown a City on Edge

AFP (Aug. 19, 2014) Residents of Sierra Leone's capital voice their fears as the Ebola virus sweeps through west Africa. Duration: 00:56 Video provided by AFP
Powered by NewsLook.com
101-Year-Old Working Man Has All The Advice You Need

101-Year-Old Working Man Has All The Advice You Need

Newsy (Aug. 19, 2014) Herman Goldman has worked at the same lighting store for almost 75 years. Find out his secrets to a happy, productive life. Video provided by Newsy
Powered by NewsLook.com
Researcher Testing on-Field Concussion Scanners

Researcher Testing on-Field Concussion Scanners

AP (Aug. 19, 2014) Four Texas high school football programs are trying out an experimental system designed to diagnose concussions on the field. The technology is in response to growing concern over head trauma in America's most watched sport. (Aug. 19) Video provided by AP
Powered by NewsLook.com
American Ebola Patient Apparently Improving, Outbreak Is Not

American Ebola Patient Apparently Improving, Outbreak Is Not

Newsy (Aug. 19, 2014) Nancy Writebol, an American missionary who contracted Ebola, is apparently getting better, according to her husband. The outbreak, however, is not. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins