Novel DNA repair mechanism brings new horizons

Estimated structure of the nucleosomal DNA loops, which are temporarily formed during transcription of chromatin containing intact DNA by RNA polymerase II (Pol II). In the presence of a single-strand DNA break, the loop structure likely changes, preventing rotation of the RNA polymerase along the DNA helix (orange arrow). CREDIT Nadezhda S. Gerasimova et al

Estimated structure of the nucleosomal DNA loops, which are temporarily formed during transcription of chromatin containing intact DNA by RNA polymerase II (Pol II). In the presence of a single-strand DNA break, the loop structure likely changes, preventing rotation of the RNA polymerase along the DNA helix (orange arrow).
CREDIT
Nadezhda S. Gerasimova et al

Researchers from the Lomonosov Moscow State University discovered a new mechanism of DNA repair, which will help to treat and to prevent diseases in the future

The DNA molecule is chemically unstable giving rise to DNA lesions of different nature. That is why DNA damage detection, signaling and repair, collectively known as the DNA damage response, are needed.

A group of researchers, lead by Vasily M. Studitsky, professor at the Lomonosov Moscow State University, discovered a new mechanism of DNA repair, which opens up new perspectives for the treatment and prevention of neurodegenerative diseases. The article describing their discovery is published in AAAS’ first open access online-only journal Science Advances.

“In higher organisms DNA is bound with proteins in complexes called the nucleosome. Every ~200 base pairs are organized in nucleosomes, consisting of eight histone proteins, which, like the thread on the bobbin, wound double helix of DNA, which is coiled into two supercoiled loops. Part of the surface of the DNA helix is hidden, because it interacts with histones. Our entire genome is packed this way, except for the areas, from which the information is being currently read”, — says Vasily M. Studitsky , who is the leading researcher and the head of the Laboratory of Regulation of Transcription and Replication at the Biological Faculty of the Lomonosov Moscow State University.

The dense packing allows DNA molecule with a length of about two meters to fit into a microscopic cell nucleus, but it makes significant surfaces of the DNA inaccessible for the repair enzymes — the proteins that manage the “repair” of damaged DNA regions. The damage of the DNA, if not repaired, leads to accumulation of mutations, cell death, and to the development of various diseases, including neurodegenerative, e.g. Alzheimer’s disease.

A group of researchers, lead by Vasily M. Studitsky, studied the mechanism of detection of single-stranded DNA breaks at which the connection is lost between nucleotides on one strand in the places where the DNA is associated with histones.

Scientists know quite a lot about the mechanism of the repair. It is known that for the synthesis of a protein, information written in the genetic code, which could be imagined as the manual for its assembly where triples of nucleotides match certain amino acids, should be taken out of the nucleus into the cytoplasm of the cell.

Thin and long strand of the DNA is packed in the nucleus and can tear at the exit to the outside. Moreover, it cannot be sacrificed as the cell’s nuclear DNA is is only present in two copies. Therefore, when it is necessary to synthesize specific protein, small region of DNA is unwound, the two strands are disconnected, and the information on the protein structure with one of the DNA strands is written in form of RNA, single-stranded molecule. The mRNA molecule, which serves as the template for making a protein, is synthesized by the principle of complementarity: each nucleotide pair corresponds to another one.

During the transcription of information (its rewriting into RNA) the RNA polymerase enzyme “rides” on the DNA chain, and stops when it finds the break. Like a proofreader of a text, RNA polymerase after it is stalled, triggers a cascade of reactions, resulting in the repair enzymes fixing the damaged area. At the same time, the RNA polymerase cannot detect discontinuities present in the other DNA strand.

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Tsukuba scientists reverse aging in human cell lines and give theory of aging a new lease of life

via medicalxpress.com

via medicalxpress.com

If proven, it could result in glycine supplements giving our older population a new lease of life.

Can the process of aging be delayed or even reversed? Research led by specially appointed Professor Jun-Ichi Hayashi from the University of Tsukuba in Japan has shown that, in human cell lines at least, it can. They also found that the regulation of two genes involved with the production of glycine, the smallest and simplest amino acid, is partly responsible for some of the characteristics of aging.

Professor Hayashi and his team made this exciting discovery while in the process of addressing some controversial issues surrounding a popular theory of aging.

This theory, the mitochondrial theory of aging, proposes that age-associated mitochondrial defects are controlled by the accumulation of mutations in the mitochondrial DNA.

Abnormal mitochondrial function is one of the hallmarks of aging in many species, including humans. This is mostly due to the fact that the mitochondrion is the so-called powerhouse of the cell as it produces energy in a process called cellular respiration. Damage to the mitochondrial DNA results in changes or mutations in the DNA sequence. Accumulation of these changes is associated with a reduced lifespan and early onset of aging-related characteristics such as weight and hair loss, curvature of the spine and osteoporosis.

There is, however, a growing body of conflicting evidence that has raised doubts about the validity of this theory. The Tsukuba team in particular has performed some compelling research that has led them to propose that age-associated mitochondrial defects are not controlled by the accumulation of mutations in the mitochondrial DNA but by another form of genetic regulation. The research, published this month in the prestigious journal Nature’s ‘Scientific Reports’, looked at the function of the mitochondria in human fibroblast cell lines derived from young people (ranging in age from a fetus to a 12 year old) and elderly people (ranging in age from 80-97 years old). The researchers compared the mitochondrial respiration and the amount of DNA damage in the mitochondria of the two groups, expecting respiration to be reduced and DNA damage to be increased in the cells from the elderly group. While the elderly group had reduced respiration, in accordance with the current theory, there was, however, no difference in the amount of DNA damage between the elderly and young groups of cells. This led the researchers to propose that another form of genetic regulation, epigenetic regulation, may be responsible for the age-associated effects seen in the mitochondria.

Epigenetic regulation refers to changes, such as the addition of chemical structures or proteins, which alter the physical structure of the DNA, resulting in genes turning on or off.  Unlike mutations, these changes do not affect the DNA sequence itself. If this theory is correct, then genetically reprogramming the cells to an embryonic stem cell–like state would remove any epigenetic changes associated with the mitochondrial DNA. In order to test this theory, the researchers reprogrammed human fibroblast cell lines derived from young and elderly people to an embryonic stem cell-like state. These cells were then turned back into fibroblasts and their mitochondrial respiratory function examined. Incredibly, the age-associated defects had been reversed – all of the fibroblasts had respiration rates comparable to those of the fetal fibroblast cell line, irrespective of whether they were derived from young or elderly people. This indicates that the aging process in the mitochondrion is controlled by epigenetic regulation, not by mutations.

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New blood test determines whether you have or are likely to get cancer

DNA damage resulting in multiple broken chromosomes (Photo credit: Wikipedia)

DNA damage resulting in multiple broken chromosomes (Photo credit: Wikipedia)

 New research in The FASEB Journal suggests that white blood cells exposed to UVA light in agar, to induce DNA damage, can predict if one has or is at risk for cancer

A new research report published in the October 2014 issue of The FASEB Journal may make the early detection of cancer as easy as a simple blood test. This test, called the “lymphocyte genome sensitivity” (LGS) test, could not only detect some cancers earlier than ever before, but it may eliminate the need for some types of biopsies, as well as identify those more likely to develop cancer in the future.

“The test could allow earlier cancer detection, so helping to save peoples’ lives,” said Diana Anderson, a researcher involved in the work from the School of Life Sciences at the University of Bradford in West Yorkshire, United Kingdom.

To develop this test, Anderson and colleagues took blood samples from a group of people that included healthy individuals, cancer patients and people believed to be at a higher risk than normal to develop cancer. White blood cells (lymphocytes) in these samples were examined in a Comet test, by embedding the cells in a jelly-like substance, called agar, on a microscope slide. In this test, damage to the genetic material (DNA) of the cells was caused by treatment with ultraviolet (UVA) light. This damage was observed in the form of DNA pieces being pulled within the agar in an electric field toward the positive end of the field. This caused a comet-like tail, and the longer the tail the more DNA damage. Different thicknesses of the agar were applied to the slides. In healthy people, as different thicknesses were added, DNA-damaged tail responses returned to normal levels. In cancer patients, DNA-damaged tail responses remained high and in those people who might develop pre-cancerous diseases, tail responses were in between. This means that people with cancer have DNA which is more easily damaged by UVA than do other people, so the test shows the sensitivity to damage of all the genome in a cell. The LGS test has been used to examine blood samples from cancer patients with melanoma, colon cancer and lung cancer, and all gave the same outcomes.

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Key to Aging Immune System Is Discovered

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. - via UCSF

Molecular tags of DNA damage are highlighted in green in blood-forming stem cells. – via UCSF

There’s a good reason people over 60 are not donor candidates for bone marrow transplantation.

The immune system ages and weakens with time, making the elderly prone to life-threatening infection and other maladies, and a UC San Francisco research team now has discovered a reason why.

“We have found the cellular mechanism responsible for the inability of blood-forming cells to maintain blood production over time in an old organism, and have identified molecular defects that could be restored for rejuvenation therapies,” said Emmanuelle Passegué, PhD, a professor of medicine and a member of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Passegué, an expert on the stem cells that give rise to the blood and immune system, led a team that published the new findings online July 30, 2014 in the journal Nature.

Blood and immune cells are short-lived, and unlike most tissues, must be constantly replenished. The cells that must keep producing them throughout a lifetime are called “hematopoietic stem cells.” Through cycles of cell division these stem cells preserve their own numbers and generate the daughter cells that give rise to replacement blood and immune cells. But the hematopoietic stem cells falter with age, because they lose the ability to replicate their DNA accurately and efficiently during cell division, Passegué’s lab team determined.

Especially vulnerable to the breakdown, the researchers discovered in their new study of old mice, are transplanted, aging, blood-forming stem cells, which lack the ability to make B cells of the immune system. These B cells make antibodies to help us fight all sorts of microbial infections, including bacteria that cause pneumonia, a leading killer of the elderly.

In old blood-forming stem cells, the researchers found a scarcity of specific protein components needed to form a molecular machine called the mini-chromosome maintenance helicase, which unwinds double-stranded DNA so that the cell’s genetic material can be duplicated and allocated to daughter cells later in cell division. In their study the stem cells were stressed by the loss of activity of this machine and as a result were at heightened risk for DNA damage and death when forced to divide.

The researchers discovered that even after the stress associated with DNA replication, surviving, non-dividing, resting, old stem cells retained molecular tags on DNA-wrapping histone proteins, a feature often associated with DNA damage. However, the researchers determined that these old survivors could repair induced DNA damage as efficiently as young stem cells.

“Old stem cells are not just sitting there with damaged DNA ready to develop cancer, as it has long been postulated” Passegué said.

But not all was well in the old, surviving stem cells.

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Plasma tool for destroying cancer cells

via Springer

Inducing biological tissue damage with an atmospheric pressure plasma source could open the door to many applications in medicine

Plasma medicine is a new and rapidly developing area of medical technology. Specifically, understanding the interaction of so-called atmospheric pressure plasma jets with biological tissues could help to use them in medical practice. Under the supervision of Sylwia Ptasinska from the University of Notre Dame, in Indiana, USA, Xu Han and colleagues conducted a quantitative and qualitative study of the different types of DNA damage induced by atmospheric pressure plasma exposure, the paper is published in EPJ D as part of a special issue on nanoscale insights into Ion Beam Cancer Therapy. This approach, they hope, could ultimately lead to devising alternative tools for cancer therapy as well as applications in hospital hygiene, dental care, skin diseases, antifungal care, chronic wounds and cosmetics treatments.

To investigate the DNA damage from the so-called non-thermal Atmospheric Pressure Plasma Jet (APPJ), the team adopted a common technique used in biochemistry, called agarose gel electrophoresis. They studied the nature and level of DNA damage by plasma species, so-called reactive radicals, under two different conditions of the helium plasma source with different parameters of electric pulses.

They also identified the effect of water on DNA damage. To do so, they examined the role of reactive radicals involved in DNA damage processes occurring in an aqueous environment. They then compared them to previous results obtained in dry DNA samples.

The next step would involve investigating plasma made from helium mixtures with different molecular ratios of other gases, such as oxygen, nitrous oxide, carbon dioxide and steam, under different plasma source conditions. The addition of another gas is expected to increase the level of radical species, such as reactive oxygen species and reactive nitrogen species, known to produce severe DNA damage. These could, ultimately, help to destroy cancerous tumour cells.

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