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

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:

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

Peter Tarr | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Don't Give the Slightest Chance to Toxic Elements in Medicinal Products
23.03.2018 | Physikalisch-Technische Bundesanstalt (PTB)

nachricht North and South Cooperation to Combat Tuberculosis
22.03.2018 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Space observation with radar to secure Germany's space infrastructure

Satellites in near-Earth orbit are at risk due to the steady increase in space debris. But their mission in the areas of telecommunications, navigation or weather forecasts is essential for society. Fraunhofer FHR therefore develops radar-based systems which allow the detection, tracking and cataloging of even the smallest particles of debris. Satellite operators who have access to our data are in a better position to plan evasive maneuvers and prevent destructive collisions. From April, 25-29 2018, Fraunhofer FHR and its partners will exhibit the complementary radar systems TIRA and GESTRA as well as the latest radar techniques for space observation across three stands at the ILA Berlin.

The "traffic situation" in space is very tense: the Earth is currently being orbited not only by countless satellites but also by a large volume of space...

Im Focus: Researchers Discover New Anti-Cancer Protein

An international team of researchers has discovered a new anti-cancer protein. The protein, called LHPP, prevents the uncontrolled proliferation of cancer cells in the liver. The researchers led by Prof. Michael N. Hall from the Biozentrum, University of Basel, report in “Nature” that LHPP can also serve as a biomarker for the diagnosis and prognosis of liver cancer.

The incidence of liver cancer, also known as hepatocellular carcinoma, is steadily increasing. In the last twenty years, the number of cases has almost doubled...

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

New solar solutions for sustainable buildings and cities

23.03.2018 | Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

Latest News

For graphite pellets, just add elbow grease

23.03.2018 | Materials Sciences

Unique communication strategy discovered in stem cell pathway controlling plant growth

23.03.2018 | Agricultural and Forestry Science

Sharpening the X-ray view of the nanocosm

23.03.2018 | Physics and Astronomy

Science & Research
Overview of more VideoLinks >>>