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:1/20/2017)... ... January 20, 2017 , ... Yisrayl Hawkins, Pastor and Overseer at The House of Yahweh ... across the world. Yisrayl says this generation is a time like no other and society ... the Bible. , Yisrayl says he does not want to sound like an old bible ...
(Date:1/20/2017)... Boca Raton, FL (PRWEB) , ... January 20, ... ... creating nutritional and wellness products to enhance people’s everyday lives, recently attended the ... major retail buyers. , ATP Science is known for its large range of ...
(Date:1/20/2017)... ... January 20, 2017 , ... “Mary Magdalene: Grace is Greater than ... the woman who witnessed Jesus Christ firsthand. “Mary Magdalene: Grace is Greater than Sin” ... career as an educator interacting with countless women who had little knowledge of the ...
(Date:1/20/2017)... ... 20, 2017 , ... “Christmas in Suffolk”: a story of love, secrets, ... lives in Lafayette, Indiana where she works in a daycare and looks for inspiration ... Published by Christian Faith Publishing, Sara Seymour’s new book is an adventure of love ...
(Date:1/19/2017)... ... ... Today, the Centers for Medicare & Medicaid Services (CMS) announced over 359,000 clinicians ... Clinicians who participate in APMs are paid for the quality of care they give ... build a system that delivers better care and one in which clinicians work together ...
Breaking Medicine News(10 mins):
(Date:1/20/2017)... 20, 2017  Palladian Health, a leading provider ... launch of an opioid management program which assists ... and helps stem the growing tide of dependence ... treat chronic non-cancer pain (back pain, neck pain, ... lack of evidence regarding long-term effectiveness. ...
(Date:1/20/2017)... Avillion LLP, a co-developer and financier of late-stage pharmaceutical product ... as Chief Medical Officer. Dr Weinberg will be based in ... ... than 17 years as a pharmaceutical and biotech executive with experience ... course of his career, he has interfaced with the US Food ...
(Date:1/19/2017)... , Jan. 19, 2017 Report Details ... Devices Market? Which areas are going to grow at ... revenues to 2026, assessing data, trends, opportunities and prospects. ... graphs. Discover the most lucrative areas in the industry ... you assess forecasted sales across the all the major ...
Breaking Medicine Technology: