Three very good pieces of biological research

The first is important for space flight and radiation because there may be a way to engineer a biological protection against leukemia by inhibiting a gene called Puma that allows stem cell cancer mutations survival. 

Public release date: 31-Jul-2010
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Contact: Penny Fannin
fannin@wehi.edu.au
61-393-452-345
Walter and Eliza Hall Institute

Missing Puma reveals cancer conundrum

		IMAGE: Professor Andreas Strasser from the Walter and Eliza Hall Institute in Melbourne, Australia, has made a discovery that has upended scientists’ understanding of programmed cell death and its role in... Click here for more information.

Walter and Eliza Hall Institute researchers in Melbourne, Australia, have made a discovery that has upended scientists' understanding of programmed cell death and its role in tumour formation.

Programmed cell death, also called apoptosis, is an important process in human biology as it removes unwanted and damaged cells from our bodies. This process protects us against cancer development and autoimmune disease.

The research team's discovery, led by Professor Andreas Strasser from the institute's Molecular Genetics of Cancer Division, has implications for the understanding of how cancers develop and will inform the ongoing development of a new class of anti-cancer drugs called BH3 mimetics.

"Until now everybody believed that a failure of damaged cells to undergo suicide allowed mutated cells to proliferate, which contributes to tumour development," Professor Strasser said. "That's certainly still true but we discovered that, in certain settings, the opposite holds: the body's natural cell-suicide program can fuel tumour development."

The research team's experiments revealed that repeated cycles of cellular depletion and tissue regeneration, by activating stem cells, could promote tumour development.

In situations where the DNA in many cells is damaged, such as when the body is repeatedly exposed to low doses of radiation, there are repeated cycles of cell death in the body's tissues. "Attempts by the body's stem cells to repopulate the depleted tissue can then actually drive the tumour development," Professor Strasser said. "That's because the radiation, while killing many cells within a tissue, will create mutations in some of the surviving stem cells. When such abnormal (mutated) stem cells repopulate the tissue, they will divide many times and this can promote the development of tumours."

The research, done in collaboration with Dr Ewa Michalak, Dr Cassandra Vandenberg, Mr Alex Delbridge, Dr Li Wu, Dr Clare Scott and Professor Jerry Adams, is published in today's issue of the international journal Genes and Development.

Crucial to the team's research was an understanding of what happens to mice exposed to radiation when a gene called Puma is missing. "If normal mice (which have the Puma gene) are given a low dose of radiation it destroys around 80 per cent of the white blood cells," Professor Strasser said. "That does not kill the mouse but it does mean the stem cells in the bone marrow have to work extra hard to replenish the blood system. This can lead to the formation of tumours of white blood cells, called leukaemias, if the stem cells doing the repopulating have cancer-causing mutations.

"The surprise was that mice that don't carry the Puma gene are protected from this type of tumour development. Puma is essential for the death of cells that have damaged DNA. If mice don't have the Puma gene when they receive low doses of radiation the white blood cells are not destroyed, so you don't force mutated stem cells to become activated (and divide) to replenish the blood system."

Professor Strasser said the research suggested that the risk of cancer was increased in people who experienced cycles of tissue destruction followed by tissue re-population by stem cells. "Such cycles may account for the liver cancers frequently associated with viral (hepatitis C) infection or alcohol-related liver damage." The research also helps explain the so-called secondary cancers that sometimes arise in patients who were cured of their primary cancer by chemotherapeutic drugs that cause DNA damage."

The findings will also inform the ongoing development of a new class of anti-cancer drugs called BH3 mimetics. These drugs are designed to kill cancer cells. "Chronic exposure to such drugs could lead to the death of large numbers of normal cells that would then need to be replaced," Professor Strasser said. "In certain circumstances this could promote the development of secondary cancers, particularly if patients are receiving treatments such as chemotherapy or gamma-radiation that can lead to cancer-causing mutations in stem cells."

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The research was supported by the National Health and Medical Research Council, the Leukemia and Lymphoma Society, the National Institutes of Health (US), the Juvenile Diabetes Research Foundation, Cancer Council Victoria and the Victorian Government.

The second and third regard regulatory functions that protect genomic integrity. This class of research coming increasingly to the forefront as science uncovers a remarkable network of a sort of metagenome that regulates genetic replication from the "outside." This involves a whole host of molecules, especially small fragments of regulatory RNA as evidenced below.

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Contact: John Ascenzi
Ascenzi@email.chop.edu
267-426-6055
Children's Hospital of Philadelphia 

Red blood cells have a tiny but effective protector -- microRNA

Genetic molecules resist chemical stress, may have wider roles

Pediatric researchers have discovered a new biological pathway in which small segments of RNA, called microRNA, help protect red blood cells from injury caused by chemicals called free radicals. The microRNA seems to have only a modest role when red blood cells experience normal conditions, but steps into action when the cells are threatened by oxidant stress.

Led by hematologist Mitchell Weiss, M.D., Ph.D., of The Children's Hospital of Philadelphia, the current study describes how a particular microRNA fine-tunes gene activity by acting on an unexpected signaling pathway.

The study appears in the August 1 issue of the journal Genes & Development, simultaneously with a similar study of microRNAs and red blood cells by a University of Texas team led by Eric Olson, Ph.D. The two studies reinforce each other, said Weiss.

MicroRNAs are single-stranded molecules of ribonucleic acid (RNA) averaging only 22 nucleotides long. Scientists estimate that 500 to 1000 microRNAs exist in the human genome. First characterized in the early 1990s, they received their current name in 2001. Over the past decade, scientists have increasingly recognized that microRNAs play a crucial role in regulating genes, most typically by attaching to a piece of messenger RNA and blocking it from being translated into a protein, but many details remain to be discovered.

"Although microRNAs affect the formation and function of most or all tissues, for most microRNAs, we don't know their precise mechanisms of action," said Weiss. "In this case we already knew this microRNA, called miR-451, regulates red blood cells in zebrafish and mice, and because it is highly conserved in evolution, we presume it operates in humans as well. But its functional roles were poorly understood."

By investigating how microRNAs influence red blood cell development, Weiss and colleagues aimed to understand how such development goes wrong in hemolytic anemia, in which red blood cells are destroyed in large numbers, or in disorders of abnormal blood cell production. The current study used knockout mice—bioengineered animals in which the miR-451 gene was removed and could not function.

They found that preventing the activity of miR-451 produced only modest effects—mild anemia in the mice—but when the team subjected mice to oxidant stress by dosing them with a drug that produces free radicals, the mice had profound anemia. The oxygen radicals attacked hemoglobin, the iron-carrying molecule in red blood cells.

"This is a common theme in microRNAs—frequently, they don't play a central role during tissue formation or normal conditions, but they have a strong protective effect when an organism is stressed," said Weiss. "Over evolutionary time, red blood cells have evolved ways to protect themselves; one of those ways is the action of microRNA."

Weiss's team found that miR-451, acting through intermediate steps on a signaling pathway, affects a key protein, FoxO3. As a transcription factor, FoxO3 regulates hundreds of genes; in this case, FoxO3 stimulates specific genes that protect red blood cells from oxidant stress. The knockout mice in this study, having lost miR-451's function, showed impaired FoxO3 activity, and less ability to protect their red blood cells.

The regulatory pathway seen here, Weiss added, may have medical implications beyond blood cell development. "This finding does not have immediate clinical application for patients with blood diseases, but it sheds light on how microRNAs fine tune physiological functions in different contexts," said Weiss. FoxO3 regulates anti-oxidant functions in heart cells and also acts as a tumor suppressor, so miR-451 may have an important role in heart protection and in fighting cancers. "Further studies may broaden our knowledge of how this microRNA may defend the body against disease," he added.

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The National Institutes of Health, the Roche Foundation for Anemia Research and the March of Dimes Foundation provided grant support for this study. Weiss's co-authors included Barry H. Paw, M.D., Ph.D., of Brigham and Women's Hospital and Harvard Medical School; Duonan Yu, Camila O. dos Santos, and several other colleagues from The Children's Hospital of Philadelphia; and collaborators from Northwestern University, Chicago; Mount Sinai School of Medicine, New York City; and the Amnis Corporation, Seattle.

"miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta," Genes and Development, published online July 31, 2010, in print issue on Aug. 1, 2010. doi: 10.1101/gad.1942110.

About The Children's Hospital of Philadelphia: The Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children's Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 460-bed hospital recognition as a leading advocate for children and adolescents. For more information, visithttp://www.chop.edu.

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ublic release date: 1-Aug-2010
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Contact: Blaine Friedlander
bpf2@cornell.edu
607-254-8093
Cornell University

'Guardian of the genome': Protein helps prevent damaged DNA in yeast

ITHACA, N.Y. — Like a scout that runs ahead to spot signs of damage or danger, a protein in yeast safeguards the yeast cells' genome during replication -- a process vulnerable to errors when DNA is copied -- according to new Cornell research.

Researchers from Cornell University's Weill Institute for Cell and Molecular Biology have discovered how a protein called Mec1 plays the role of "guardian of the genome," explained Marcus Smolka, assistant professor of molecular biology and genetics. The findings "DNA Damage Signaling Recruits the Rtt107-Slx4 Scaffolds via Dpb11 to Mediate Replication Stress Response," are detailed in the journal Molecular Cell (July 30, 2010).

Previous studies have shown that cells lacking Mec1 accumulate damaged DNA and become more sensitive to agents that interfere with replication. The researchers report that the Mec1 protein monitors and repairs the machinery responsible for replicating the DNA. At times, when DNA becomes damaged, the replication machinery can actually detach from the DNA -- like a train coming off a track -- but Mec1 coordinates the repair of the machinery and the DNA itself, allowing it to restart and continue replicating.

"Mec1 organizes the cell's response against things that jeopardize the integrity of the genome," Smolka said.

During the replication process, Mec1 accumulates at trouble spots such as lesions in the DNA or other blocks to replication. Mec1 is known as a kinase, a type of enzyme that modifies other proteins by adding a phosphate group to them (a process called phosphorylation), which then leads to a functional change in the protein. The researchers report that Mec1 adds a phosphate group to a protein known as Slx4, which then triggers Slx4 to anchor to the replication machinery. Slx4 then can employ a variety of tools to repair DNA and the replication machinery.

The findings are important because researchers have discovered counterparts (called orthologues) to Mec1, other related proteins with similar biological pathways in humans. Also, mutations to the human genes that produce Mec1 and related proteins can lead to cancer predisposition and neurological disorders. At the same time, cancer cells employ their own similar replication repair system, so understanding the process may help researchers design interventions that interrupt replication of cancer DNA.

Recently, other researchers discovered that the human version of Mec1, called ATR, phosphorylates a protein that is the human counterpart to Slx4. The next step, Smolka said, will be to see if after phosphorylation the human Slx4 also anchors to the replication machinery to repair any damaged machinery or DNA.

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Co-authors include Patrice Ohouo, a graduate student in biochemistry, molecular and cell biology; Francisco M. Bastos de Oliveira, a postdoctoral researcher; and Beatriz Almeida, a research support specialist; all members of Smolka's lab.

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