Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Protein involved in DNA replication, centrosome regulation linked to dwarfism, small brain size

01.08.2012
Orc1 mutations may explain pathology in manifestations of Meier-Gorlin syndrome

Cold Spring Harbor, NY – Research published Aug. 1 by scientists at Cold Spring Harbor Laboratory (CSHL) links gene mutations found in some patients with Meier-Gorlin syndrome (MGS) with specific cellular dysfunctions that are thought to give rise to a particularly extreme version of dwarfism, small brain size, and other manifestations of abnormal growth which generally characterize that rare condition.

Although only 53 cases of Meier-Gorlin syndrome have been reported in the medical literature since the first patient was described in 1959, it is a malady whose mechanisms are bringing to light new functions for some of the cellular processes common to all life. Pathology related to MGS is traced in the new research to one of these, the fundamental process called mitosis in which cells replicate their genetic material and prepare to divide into two identical "daughter" cells.

CSHL President and Professor Bruce Stillman, Ph.D., a cancer biologist who has made seminal discoveries over three decades that have helped reveal the exquisite choreography of how chromosomes are duplicated in cells, led the new research, which suggests how, during mitosis, mutant versions of a protein called Orc1 contribute in two distinct ways to severe MGS pathology. The research is published online ahead of print in Genes & Development.

Components of the cellular replication machinery

Orc1 is the largest of six proteins that form parts of a cellular machine called the origin recognition complex, or ORC. As Stillman and others discovered 20 years ago, ORC in human cells attaches to DNA at specific locations throughout the genome when a cell is preparing to duplicate its genetic information and go through cell division. These locations are called replication start sites or origins. When ORC and several other helper proteins attach at these positions, each of the assembled groups of proteins is said to form a pre-replication complex (pre-RC).

When pre-RCs have attached at all of the "start" sites throughout the genome -- a process called licensing -- cells can then begin to copy the double helix of DNA to produce two copies, one for each daughter cell. ORC enables a cell to keep track of its DNA replication and this is essential because the genetic material must be copied once, and only once.

Other roles for ORC, including centrosome regulation

Over the years, new roles for many of the ORC proteins have been found within the cell. Not only are they involved in DNA replication; as Stillman (2009) and others have shown, a number of them are also known to be involved in regulation of a cellular organ called the centrosome. Floating inside the cell's watery cytoplasm, the centrosome helps regulate the cell's progression through the cell-cycle. It ensures that the duplicated chromosomes are segregated evenly to the daughter cells. During replication, it organizes the threadlike microtubules that form a delicate spindle that segregates the two identical sets of chromosomes. Serving as anchor points for those "threads" are tiny structures inside the centrosome called centrioles. Just like DNA, which must be licensed to insure it is only copied once per cell cycle, so must the centrosome and centrioles be licensed for proper regulation of cell division.

The centrosome also plays a role in establishing cell outgrowths, such as axons in brain cells and cilia in many other cells of the body.

Mutant ORC proteins are linked to MGS pathology

Stillman and Manzar Hossain, Ph.D., a postdoctoral student in the Stillman lab, have followed up clues in recent research linking mutations in the genes encoding proteins of the pre-RC, including Orc1, with mutations found in Meier-Gorlin syndrome patients. In a study published this past February, a multinational research team noted the relationship of such mutations to various manifestations of the pathology seen in 35 MGS patients. They noted that MGS patients with mutations in Orc1 were the shortest and had the smallest brain size.

The new study by Hossain and Stillman describes how Orc1 mutations cause cellular dysfunctions that contribute directly to the most severe instances of dwarfism and small brain size.

New findings about centrosome and centriole dysfunction in MGS

In their dissection of Orc1, Hossain and Stillman discovered that different domains of the Orc1 protein control centrosome copy number and DNA replication; and that both are involved in MGS pathology.

The CSHL scientists suggest that centrosome reduplication as well as dysregulation of DNA replication (in which Orc1 is also involved) are directly associated with the more severe manifestation of dwarfism and microcephaly, or abnormally small brain size, seen in the most pronounced MGS cases.

For the first time, they observed that when the Orc1-encoding gene is mutated in a manner observed in MGS patients, the role normally played by the Orc1 protein in preventing the centrosome from re-duplicating itself is disturbed. By causing defects in the duplication of centrosomes, processes such as cell division and cell signaling can go awry, leading to the severe growth defects found in Orc1 MGS patients.

This research has significant implications for processes that control body and brain size; how tissues come to be the size that they are is a little understood area of biology. Studying how mutations in centrosome biology affect tissue and body size may lead to insights into this regulation, Stillman suggests. He also notes that while Orc1 MGS individuals have a relatively small brain, they display normal intelligence, suggesting the enormous potential of the human brain.

"Meier-Gorlin syndrome mutations disrupt an Orc1 CDK inhibitory domain and cause centrosome reduplication" appears online a head of print on August 14, 2012 in Genes & Development. The authors are: Manzar Hossain and Bruce Stillman. The paper can be viewed online at: http://genesdev.cshlp.org

This research was supported by a grant from the National Cancer Institute [CA13106].

About Cold Spring Harbor Laboratory Founded in 1890, Cold Spring Harbor Laboratory (CSHL) has shaped contemporary biomedical research and education with programs in cancer, neuroscience, plant biology and quantitative biology. CSHL is ranked number one in the world by Thomson Reuters for impact of its research in molecular biology and genetics. The Laboratory has been home to eight Nobel Prize winners. Today, CSHL's multidisciplinary scientific community is more than 360 scientists strong and its Meetings & Courses program hosts more than 12,500 scientists from around the world each year to its Long Island campus and its China center. Tens of thousands more benefit from the research, reviews, and ideas published in journals and books distributed internationally by CSHL Press. The Laboratory's education arm also includes a graduate school and programs for undergraduates as well as middle and high school students and teachers. CSHL is a private, not-for-profit institution on the north shore of Long Island. For more information, visit www.cshl.edu.

Peter Tarr | EurekAlert!
Further information:
http://www.cshl.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>