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Enzyme found to limit collateral damage from immune system

Enzyme found to limit collateral damage from immune system. Science & Technology World Website

When unwanted microbes enter your body, your white blood cells rush to the scene to begin fighting them off. But much like a battalion of soldiers, the process by which the cells fight off the invaders needs to be extremely precise, otherwise healthy parts of the body could be damaged by a kind of biological friendly fire. Researchers at the University of Basel in Switzerland (UB), have just uncovered the role of a key enzyme in the process that allows white blood cells to attack with sniper-like precision.

The enzyme is called MPO, or myeloperoxidase, and is actually the compound responsible for giving a green hue to pus at infection sites. When a white blood cell approaches an invading bacterium, it releases hydrogen peroxide (H2O2). MPO converts that substance into HOCL, or hypochloric acid (better known as bleach), which acts like a tiny detonation that wipes out invaders in a radius measuring less than .1 micrometers by burning holes in them.

"Bacteria are helpless against this acid bomb," explains UB professor Dirk Bumann who co-headed the research. "As hypochloric acid is so highly reactive, the bomb reacts immediately with the closest biomolecules. It is ignited locally and does not spread to the wider surroundings. The bacteria die and the surrounding tissue is spared."

Basically, the MPO acts as a containment system that ensures that the converted hydrogen peroxide is only released in a small area.

To see just what happens when MPO is absent from the body, the researchers looked at cells from people who don't have the enzyme because of a genetic effect. In those individuals, the white blood cells still release H2O2 in the face of an invader, but it is never converted. It simply leaks out of the blood cells. This has the result of killing the bacteria, but also damaging the surrounding tissue. "The collateral damage of blood cells and tissues without MPO may cause long-term consequences such as accelerated aging and cancer, but this has not yet been systematically investigated," added UB's Nina Khanna, the other investigatory head in the study.

Additionally, the researchers found that when mice lacking MPO were infected with Salmonella, the release of H2O2 also caused tissue damage along with "exacerbated oxidative damage of host lipids and DNA."

The researchers say the findings could help lead to new treatment strategies to fight bacterial infections through the bolstering of MPO.

Their work has been published in the journal Nature Microbiology.

Scientists discover how 'super enzyme' speeds up DNA repair

Scientists discover how 'super enzyme' speeds up DNA repair  Science & Technology World Website

Scientists from the University of Sussex have discovered how an enzyme, known as PARP3, helps to accelerate the repair of DNA.

In the body, mutations can arise from DNA damage that is not repaired properly, leading to disease, including cancer and neurodegenerative disease. New research funded by the MRC and Cancer Research UK, led by the laboratories of Professor Keith Caldecott and Professor Laurence Pearl at the University of Sussex's Genome Damage and Stability Centre, has identified how the enzyme PARP3, short for poly(ADP-ribose) polymerase 3, recognises and signals the presence of broken DNA strands.

Research has shown that the PARP3 enzyme is involved in the DNA repair process and helps to maintain the integrity of the genetic code, but until now the precise DNA repair activation mechanism triggered by the enzyme was unclear.

Using multi-disciplinary expertise, Sussex scientists have identified the specific steps involved in activating the DNA repair process. When the PARP3 enzyme locates a specific site of DNA damage, it 'marks' the damaged DNA with a molecular signal.

This signal is created via a chemical change, involving the addition of a molecule called 'ADP-ribose' to the DNA. The DNA is packaged up in a complex called 'chromatin' which contains proteins; the team found that the PARP3 enzyme adds the 'ADP-ribose' molecule to one of these proteins – 'histone H2B'.

By marking the precise site of damage the enzyme flags the problem up to specialised DNA repair enzymes that will move in to repair the damage, protecting the cell from potentially dangerous DNA breaks.

The researchers believe this is a vital step towards understanding how DNA breaks are detected, signalled, and repaired, which could in the future enable scientists to create drugs which can better target certain cancers.

PARP3 is one of a superfamily of enzymes that are targeted by PARP inhibitor drugs, a new class drugs used to treat hereditary cancer, including ovarian and breast cancer. Knowledge of how the PARP3 enzyme activates DNA repair will also contribute to improving the understanding, and targeting, of PARP inhibitor drugs.

The research, which took place over four years, also involved nuclear magnetic resonance expertise in Professor Steve Matthews' group at Imperial College, London, proteomics in the lab of Dr Steve Sweet in Sussex and chromatin biology in the lab of Dr Alan Thorne at the University of Portsmouth.

Professor Keith Caldecott, who led the study, said: "This discovery highlights the value of multi-disciplinary collaborations, combining molecular and cellular biology with biochemistry and structural biology. As a result of working together, we have been able to identify how PARP3 recognises and flags the presence of broken DNA.

"This will be important for our understanding of how cells protect themselves from potentially dangerous DNA breaks. It will also help to provide insight into the mechanisms of action of a new class of PARP inhibitory anti-cancer drugs."

How enzyme complex DCC recognizes the X chromosome

How enzyme complex DCC recognizes the X chromosome  Science & Technology World Website

In male cells of the fruit fly Drosophila, the X chromosome is twice as active as in female cells. Researchers at LMU Munich have now discovered how the enzyme responsible recognises the chromosome.

In many species, the sex chromosomes are unequally distributed: in humans as well as in the model organism Drosophila melanogaster male cells only possess one X chromosome, unlike female cells, which contain two Xs. Male fruit flies compensate for this short-coming by doubling the activity of their single X chromosome. This vital process is controlled by the enzyme complex known as DCC (dosage compensation complex). "How this regulator distinguishes the X chromosome from all the other chromosomes has remained unsolved for a long time", says LMU biologist Professor Peter Becker from the Biomedical Center (BMC) at the LMU. Becker's team has now reported on an important conceptual and methodological breakthrough: the researchers demonstrate that a key role in the process is played by the fine detail of DNA shape. In addition, they have also identified the part of the enzyme complex that binds to the X chromosome. The insights gained from Drosophila are not only important for understanding the gene regulation in flies, but also illustrate fundamental mechanisms that affect all life forms in similar ways. The scientists have reported their results in the prestigious journal Nature.

Some 300 binding sites for the DCC enzyme complex to the X chromosome are known to date. From their DNA sequences, researchers have calculated the recognition sequence (known as the consensus sequence), in which each position is occupied by the particular DNA building block, which occurs most frequently in comparison with all binding sites. "The problem is that the consensus sequence signature that can be robustly identified at most DCC binding sites is also present some thousands of times on all other chromosomes", states Becker. "For this reason, we have previously been unable to predict whether a particular DNA sequence is actually a functional DCC binding site or not."

A novel strategy Becker describes as 'genome-wide biochemical analysis' has now provided a major step forward. The researchers were able to demonstrate that one specific building block from the DCC regulator – the MSL2 protein – is sufficient to reliably bind the consensus sequence. Furthermore, the MSL2 protein actually possesses two DNA binding domains, of which one binds to a DNA sequence, which extends the previously known consensus sequence. "We called this new signature 'PionX', because it turns out that these binding sites represent the first DCC contact points to the X chromosome. There are, however, some 2,700 sequences in the fly genome that resemble the PionX signature a lot, of which only 57 function as genuine MSL2 binding sites", relates Becker.

"The decisive breakthrough was achieved by BMC bioinformaticians, first and foremost Tobias Straub, who calculated how the sequence of the base pairs affected the intricate structure of the DNA, also known as 'DNA shape'", states Becker. The researchers identified a particular shape shared by PionX sequences that is preferably recognised by the MSL2 protein. This structure makes the vital difference: it distinguishes the binding sites on the X chromosome from all others, enabling a selective interaction and regulation by the dosage compensation complex. "Our work has decisively advanced the understanding of chromosome-wide regulation during the process of X chromosome dosage compensation", states Becker. "However, our current progress only explains part of the X chromosomal recognition in vivo and we still have to improve our ability to distinguish correct DCC binding sites from 'false-positive' and false-negative' sites identified by our algorithm." In the future, the researchers intend to further refine the genome-wide biochemical analysis strategy, in order to better understand the recognition of the X chromosome by the DCC.



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