Navigation Links
Molecular gate that could keep cancer cells locked up
Date:7/31/2014

In a study published today in Genes & Development, Dr Christian Speck from the MRC Clinical Sciences Centre's DNA Replication group, in collaboration with Brookhaven National Laboratory (BNL), New York, reveal the intricate mechanisms involved in the enzyme that governs DNA duplication during cell division. By developing a sophisticated system using synthetic, chemical and structural biology approaches, the study reveals how a key enzyme involved in duplicating genetic information embraces DNA through a gated system, which opens up at precise positions allowing for a highly regulated replication process. This work enhances current understanding of an essential biological process and suggests a route for stopping cell division in disease such as cancer.

When a cell divides, genetic information is duplicated in a process known as DNA replication. For this to occur, a 'replication machine' is assembled on top of the DNA prior to duplication. A protein complex known as ORC that recognises the DNA replication origin initiates the whole process. Next, an enzyme, MCM2-7 helicase, whose role is to unwind and separate the two strands of the DNA helix, is loaded onto the DNA by the machine system ORC. The helicase is a ring shaped enzyme composed of six subunits (hexamer), though how the ring structure opens and encircles the DNA has, until now, remained a mystery.

Initial theories within in field assumed the helicase to exist in an open ring conformation. Speck's team argued that this would undoubtedly lead to poorly regulated DNA replication with no control or specificity. To examine the helicase activity in more detail, Jingchuan Sun at BNL used an electron microscope and revealed, contrary to initial theories, the helicase actually existed as a closed ring conformation.

To pinpoint where within the six subunits, the helicase opens to encompass the DNA, the team generated linkages that blocked ring opening at various positions. They found that if they blocked one specific interface, between MCM2 and MCM5, DNA could not enter. A small molecule called rapamycin brings the linkages together; such a molecular switch can be used to control DNA entry to the MCM ring and subsequent DNA replication. "Both in the context of our in vitro and in vivo experiments, we showed that opening of the MCM2/MCM5 interface is essential for helicase loading onto DNA," explains Christian.

"The field has known for a while that DNA can pass into the MCM2-7 ring, but has never been sure which MCM subunits are used for regulated helicase loading. By designing an elegant experiment, the Speck laboratory has now shown once and for all that the MCM2-5 is the only DNA entry point," says collaborator Huilin Li at BNL.

In eukaryotes, the MCM2-7 helicase forms a double hexamer (with another MCM2-7 unit) when it is loaded onto DNA. In this study, the group also settled the longstanding dispute surrounding whether the helicase is actually loaded as a single hexamer, which then dimerises, or is loaded as a dimer at the offset. They concluded that the helicase is in fact loaded as a single hexamer before forming a double hexamer.

In a successful collaboration that harnesses the electron microscopy expertise at BNL with the chemical biology and genetic expertise at the MRC Clinical Sciences Centre, the study addresses key questions detailing the processes involved in DNA replication. "Our work is aimed at understanding the molecular mechanism of DNA replication at a fundamental level. Yet our findings could also have important implications, possibly pointing to new ways to fight cancer, because DNA duplication is a prime target to inhibit cancer cell growth," says Christian.


'/>"/>

Contact: Christian Speck
christian.speck@imperial.ac.uk
44-208-383-3387
MRC Clinical Sciences Centre
Source:Eurekalert  

Related medicine news :

1. China Diagnostic Reagent Industry (biochemical, molecular & immunodiagnostic) 2016 Forecasts in New Research Report at ChinaMarketResearchReports.com
2. Immunotherapy, Targeted Molecular Therapies Among Promising New Treatments for Brain Tumors
3. Increasing Molecular Level Understanding of Disease State & Metabolism Drives the Molecular Diagnostics Market, According to New Report by Global Industry Analysts, Inc.
4. Global Molecular Diagnostics Market Report 2014 Edition Now Available at MarketReportsOnline.com
5. VCU receives grant to study molecular marks left by childhood adverse experiences
6. Rigid connections: Molecular basis of age-related memory loss explained
7. Global Molecular Diagnostics Market Expected to Reach USD 8.7 Billion through 2019: Transparency Market Research
8. Enzyme-inhibition could revolutionize molecular imaging
9. Molecular imaging finds novel way to knock down breast cancer
10. Molecular breast imaging protocol unmasks more cancer
11. Scientists generate long-sought molecular map of critical genetic machinery
Post Your Comments:
*Name:
*Comment:
*Email:
Related Image:
Molecular gate that could keep cancer cells locked up
(Date:2/9/2016)... ... February 09, 2016 , ... Dr. Rassouli, cosmetic dentist in Orange ... among the most popular cosmetic procedures in dentistry today, but the cost often leads ... them at risk of teeth whitening-related damage. For a limited time, Dr. Rassouli is ...
(Date:2/9/2016)... ... February 09, 2016 , ... METTLER TOLEDO ... lab personnel have a basic understanding of the techniques they use so they ... will help them reduce waste and rework to create a leaner overall lab ...
(Date:2/9/2016)... ... February 09, 2016 , ... Two renowned photographers, Robert Caplin (New ... adventure on the island, June 14-19, 2016, hosted by Four Seasons Resort Maui at ... After a successful debut in 2015, the Maui Photo Expedition workshop will ...
(Date:2/9/2016)... ... February 09, 2016 , ... Sir ... company , is proud to announce that many of their franchises have received ... service. The hard surface restoration franchises received customer recognition through positive reviews and ...
(Date:2/9/2016)... ... , ... Shark Finds and Kevin Harrington, and the Product Managers of AsSeenOnTV.pro are ... a newly patented product that has solved some of the basic problems golfers have faced ... dew or right after a rain shower, might understand the struggle of placing the club ...
Breaking Medicine News(10 mins):
(Date:2/9/2016)... 2016 The leader in accelerated orthodontics, OrthoAccel ... is the recipient of the 2015 Townie Choice Award ... II medical device that speeds up orthodontic tooth movement ... often associated with treatment, AcceleDent was selected by orthodontists ... Orthotown survey of the most reliable and ...
(Date:2/9/2016)... , Feb. 9, 2016  Increasingly, health care professionals ... vital signs with wireless technology. With the Vios Monitoring ... patient oversight and remotely detect problems before they become ... across in-hospital environments. the United States ... States . --> The Vios ...
(Date:2/9/2016)... , Feb. 9, 2016 The new report " ... 2015-2019" by Spearhead Acuity Business Research & Consulting group reveals that ... and neonatal market with a share of 36.4% in 2014 that ... America , the report also covers market analysis for Fetal ... Europe , Asia-Pacific , Latin ...
Breaking Medicine Technology: