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!
Molecular motors run in unison in a metal-organic framework
20.03.2019 | University of Groningen
Active substance from plant slows down aggressive eye cancer
20.03.2019 | Rheinische Friedrich-Wilhelms-Universität Bonn
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum
For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...
Physicists in the EPic Lab at University of Sussex make crucial development in global race to develop a portable atomic clock
Scientists in the Emergent Photonics Lab (EPic Lab) at the University of Sussex have made a breakthrough to a crucial element of an atomic clock - devices...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
20.03.2019 | Life Sciences
20.03.2019 | Life Sciences
20.03.2019 | Trade Fair News