Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Identify New Cause of Genomic Instability

08.08.2003


HHMI Investigator Frederick Alt


Researchers sifting through the indispensable machinery that senses and fixes broken DNA have discovered a new culprit that can induce instability in the genome and thereby set the stage for cancer to develop.

Studies in mice have shown that loss of H2AX, a gene that produces a protein called a histone that is part of the chromosomal structure, can tip the delicate balance of proteins that are curators of the human genome. When H2AX ceases to function properly, lymphomas and solid tumors can arise because errors in the genetic code are not always repaired correctly, according to the new research.

The finding may have important implications for understanding the origin of human cancers because a large number of human tumors are known to contain alterations in the region of chromosome 11 where the H2AX gene is located.



The research was reported in an article published in the August 8, 2003, issue of the journal Cell by Howard Hughes Medical Institute investigator Frederick Alt and colleagues at Children’s Hospital in Boston and Harvard Medical School. Other co-authors are from the Tufts University School of Veterinary Medicine and Brigham and Women’s Hospital.

According to Alt, previous studies by other researchers had shown that H2AX was activated when DNA breaks occur. DNA repair proteins fix genetic damage, but they are also called to action during the normal gene rearrangement that occurs in immune cells when they are readying to battle viruses and other threats.

To explore the implications of knocking out the H2AX gene, lead author Craig Bassing created a line of mice lacking both copies of the H2AX gene. “Both Craig in our lab and Andre Nussenzweig at the National Cancer Institute produced knockout strains that showed an increased level of genomic instability,” said Alt. Nussenzweig and his colleagues have published an article in the same issue of Cell on studies of their H2AX-knockout mice, and have found similar increases in genomic instability and cancer.

According to Alt, the mice lacking only H2AX genes had only a modest increase in cancer, “which is often the case for many genes that produce cancer, because they operate within a system of cellular checks and balances,” he said. “But when you eliminate two genes that may work in concert to maintain good genomic order, you see things happen that are much more dramatic.”

Thus, the researchers created a double-knockout mouse that lacked both H2AX and p53 — a gene that produces a molecular sentinel protein that suppresses proliferation of cells with damaged DNA. In previous studies, Alt and his colleagues had shown that loss of p53 in cells that lacked the DNA-repair process known as non-homologous end-joining (NHEJ) resulted in a dramatic increase in cancers.

“When we deleted both copies of H2AX and both copies of p53, we found a dramatically increased rate of tumors appearing beyond what would be seen with H2AX deficiency alone, and far, far beyond p53 deficiency alone,” said Alt. These cancers developed so rapidly that within a few months all the mice had died, he said. The resulting tumors included both lymphomas arising from aberrant immune cells — which would be common in the loss of NHEJ DNA repair function — and solid tumors, which are not normally seen when NHEJ is compromised.

The researchers also saw cancers arising from malfunction of DNA repair in mature immune cells called B cells. “These kinds of tumors are much more relevant to what goes on in a very large percentage of lymphomas in humans, and adults, in particular,” said Alt.

Alt said that the biggest surprise came when the researchers produced mice missing only one of the two copies of the H2AX gene. “Both surprising and potentially very significant for human cancers was that p53-deficient mice with deletion of one of their two copies of the H2AX gene came down with cancer much earlier,” he said. “They showed a very broad spectrum of tumors that was somewhat different than p53-deficient animals missing both H2AX genes.”

Furthermore, the studies showed that otherwise normal cells that were missing just one H2AX gene had only half the levels of H2AX and also showed genomic instability.

The possibility that only half the levels of the H2AX protein — called “haploinsufficiency” — triggers genomic instability and cancers could be highly significant, said Alt. Such a class of mutation would not have been readily detected in most searches for genes that suppress tumors in humans. Indeed, Bassing discovered that tumors in these mice still had a functioning H2AX gene.

“A major question is why haploinsufficiency of the H2AX protein can cause genomic instability and cancer,” said Alt. “One might explain that quite easily because the protein is not an enzyme, it’s a structural protein. So, if there’s half as much present, it could cause problems in monitoring breaks in the DNA and in recruiting components of the repair machinery.”

What may be especially relevant to human cancers, said Alt, is that the H2AX gene is located in a region of chromosome 11 known to be altered in many human tumors. While there are other potential cancer-causing genes in that region, he said, the current evidence from the mouse model indicates that H2AX will very likely prove a major player in cancer-causing genomic instability.

Alt and his colleagues are now collaborating with scientists at the Dana-Farber Cancer Institute to analyze the status of H2AX genes in a wide range of human cancers. “We believe that the loss of H2AX could prove a major source of the rampant instability associated with the progression of a variety of different tumors,” he said.

Contact: Jim Keeley, mailto:keeleyj@hhmi.org

Jim Keeley | Howard Hughes Medical Institute
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>