A team of Whitehead Institute scientists has discovered the surprising manner in which an enigmatic protein known as SUUR acts to control gene copy number during DNA replication. It’s a finding that could shed new light on the formation of fragile genomic regions associated with chromosomal abnormalities.
In a developing organism, few cellular processes are as critical as accurate DNA replication. When successful, replication transmits genetic material from mother to daughter cells (as occurs during mitotic cell division) or boosts DNA copy number in the cells of tissues that rely on multiple copies of the genome to increase in size. When aberrant, the process can cause genetic mutations, copy number variations, and other flaws linked to cancer and developmental disorders.
Given its importance, DNA replication is tightly regulated, primarily upon initiation at genomic sites known as origins of replication. A two-pronged structure known as a replication fork forms at an origin and moves along the double-stranded DNA, unwinding it to create two single strands for copying. Throughout the genome, however, are regions where replication is more challenging. It is likely that the DNA packaging material known as chromatin, which has been shown to be particularly dense in specific regions, poses a challenge to the progression of replication forks. Some of these regions have been found lacking replication origins and prone to DNA damage.
Whitehead Member Terry Orr-Weaver, who likens replication fork movement to that of a train moving along a DNA railroad track, has long used the fruit fly Drosophila as a model in which to study fork progression and inhibition. Her lab recently implicated the protein SUUR, produced by the SuUR gene (for “Suppressor of Under-Replication”), in impeding replication fork progression in developing and differentiating tissues.
At the time, Orr-Weaver, who is also a professor of biology at MIT, surmised that SUUR was acting as a barrier resting on the railroad track. In research published online this week in the journal Cell Reports, her lab describes a very different action for this unusual protein.
“It turns out that rather than blocking the tracks, the protein is actually moving along with the engine of the train, acting like a brakeman to either stall or derail the train,” Orr-Weaver says. “This is the first definition of a protein that has this function. It sets up regions of the genome that are under-replicated, and we think it’s what causes chromosomes to be fragile and prone to breaks.”
For Jared Nordman, a postdoctoral researcher in the Orr-Weaver lab and first author of the Cell Reports paper, this unexpected finding raises a number of additional questions. For one, it remains unclear exactly how SUUR exerts its braking function at the engine that is the replication fork. Might it destabilize the fork, or is something else happening? Another perhaps more profound question is why a protein whose sole function is to impede replication forks exists in the first place.
“We don’t really know why it’s there,” says Nordman. “Clearly, cells go to great lengths to not copy these regions of the genome, even though these regions tend to have lots of DNA damage. This is certainly another way to control DNA replication beyond just blocking initiation.”
Nordman and Orr-Weaver speculate that SUUR and its inhibition of replication fork progression is involved in a broadly conserved process known as replication timing, which controls when certain portions of the genome are duplicated during a specific phase of the cell cycle.
“We also don’t yet know why replication timing occurs,” Nordman adds. “But we do think SUUR could be having an impact on its regulation.”
This work was supported by the National Institutes of Health (grant GM57960; K99 award 1K99GM104151), the American Cancer Society, the Damon Runyon Cancer Research Foundation, the Russian Foundation for Basic Research, and the European Molecular Biology Organization.
Written by Matt Fearer
* * *
Terry Orr-Weaver’s primary affiliation is with Whitehead Institute for Biomedical Research, where her laboratory is located and all her research is conducted. She is also an American Cancer Society Research Professor of biology at the Massachusetts Institute of Technology.
* * *
“DNA Copy-Number Control through Inhibition of Replication Fork Progression”
Cell Reports, October 30, 2014 (online)
Jared T. Nordman (1), Elena N. Kozhevnikova (3,4), C. Peter Verrijzer (3), Alexey V. Pindyurin (5,6,7), Evgeniya N. Andreyeva (6), Victor V. Shloma (6), Igor F. Zhimulev (6,7), and Terry L. Orr-Weaver (1,2)
1. Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, USA
2. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02142, USA
3. Erasmus University Medical Centre, P.O. Box 1738, 3000 DR Rotterdam, the Netherlands
4. Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 10, Novosibirsk 630090, Russia
5. Netherlands Cancer Institute, Plesmanlaan 121,1066 CX Amsterdam, the Netherlands
6. Institute of Molecular and Cellular Biology,Siberian Branch of Russian Academy of Sciences, Lavrentyev Avenue 8/2, Novosibirsk 630090, Russia
7. Novosibirsk State University, Pirogova St.2, Novosibirsk 630090, Russia
Director of Communications and Public Affairs
Matt Fearer | newswise
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.
Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...
The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...
Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.
Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences