Study suggests new targets for the treatment of rare genetic disorder and cancer

Study suggests new targets for the treatment of rare genetic disorder and cancer -

The combined action of two enzymes, and Srs2 EXO1, prevents and repairs common genetic mutations in cells yeast growth, according to a new study by scientists at NYU Langone Medical Center.

Because such mechanisms are generally preserved throughout evolution, at least in part, researchers say the results suggest that a similar DNA repair kit may exist in man and could be a target for controlling certain cancers and treatment, a genetic disorder linked to a rare enzyme called Aicardi syndrome-Goutieres. Syndrome, an often fatal neurological condition, is found in only a few families in small towns in Italy, Algeria and Japan, and among the Cree Indians in North America.

In a report to be published in the journal Nature Online June 1, NYU Langone researchers, aided by colleagues from Yale University, found that the action of the paired enzyme prevents and repairs the errors made during the DNA replication, when molecular subunits called rNMPs is inserted into the DNA. The rNMPs are RNA building blocks chemical cousin of DNA, which is the key intermediate involved in making all the proteins from DNA

The researchers propose that some misguided rNMPs occur naturally -. And are repaired - that DNA is replicated during cell growth, enzymes quickly recognize these foreign intruders like lesions. If not removed, these lesions increase the probability of mutations in the DNA code, which if allowed to accumulate, create genomic instability in yeast and human cells, and may lead to cell death and immune responses promote cancer.

"Taking our cue from the yeast, which shares a third of its genetic makeup with humans, our study shows for the first time a robust safeguard mechanism of DNA repair is in place to deal with common RNMP induced mutations, "says senior study investigator and NYU Langone yeast geneticist Hannah Klein, PhD." Without a robust backup system for DNA repair, the cells will die. "

Among the key findings of the study was that one of the enzymes, Srs2, helps open the scale yeast DNA structure resembling closely linked so that another enzyme, EXO1, can cleave on rNMPs astray. These bad RNMP insertions during replication, scientists say, contaminating DNA and often fatal structural alterations. both enzymes were previously known to play a role in DNA replication and repair, but scientists say this is the first evidence of their role in the prevention and correction of derivative RNMP mutations.

Furthermore, the research team found that the Srs2 Exo1cell-repair mechanism prevents mutations of the acceleration in the already deficient yeast in a third enzyme encoded by the gene RNaseH2. This enzyme is the primary removal mechanism for rNMPs during cell growth, a major role in DNA repair. But in the deficient yeast as the RNaseH2 and Srs2 enzyme, the number of mutations, loss of chromosomes, and chromosome breaks increase of 10 times.

According to Dr. Klein, acting president of biochemistry and molecular pharmacology at NYU Langone, the study team is also the first to show how Srs2 and EXO1 backup service routine function RNMP RNaseH2 of the enzyme, highlighting the constant need nature to balance cell growth, genetic mutation and DNA repair in preventing disease and cell death.

Dr. Klein warned that if no known human counterpart Srs2 exists EXO1 is in human cells, it is likely that a repair safeguard mechanism similar DNA exists in people. And if further testing shows that its repair function can be manipulated in humans, the enzyme mechanism can be used as a basis to block or reverse derivatives cancers RNaseH2 mutations. Dr. Klein said decomposing how tumors develop in yeast cells deficient RNaseH2 is essential to develop and test potential treatments for people.

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Other research has involved RNase H2 as one of several genetic aspects of many cancers, including cancers of the bladder, brain, breast, head and neck squamous cell carcinoma and leukemia (T- and B acute lymphoblastic leukemia cells and acute myelogenous leukemia), melanomas, and seminomas.

Even more specifically, she said, the enzyme repair mechanism could be used to decrypt and address the root causes of the enzyme RNaseH2 deficit, which in humans is known to be the one of the main hereditary signatures behind Aicardi syndrome -Goutieres. The syndrome causes inflammation of the spinal cord and brain shrinkage inevitably stall the physical and mental development in early childhood. Although rare and currently incurable, the disease affects hundreds in isolated communities where inbreeding within the family took place and when both parents have RNaseH2 or other Aicardi -Goutieres related mutations.

For the study, lead investigator and yeast geneticist colleague Catherine Potenski, PhD, monitored how various mutant yeast strains grew in the laboratory, including the deficient enzyme RNaseH2 and Srs2. (Dr Klein's lab in the late 1980s was the first to isolate RNaseH2 mutations in yeast.)

Dr. Potenski, a postdoctoral researcher at NYU Langone, said yeast strains deficient in both enzymes accumulated mutations and thrive, while those only depleted the RNaseH2 enzyme were able to minimize the changes and continue to grow. However, in experiments with EXO1, disposal doped mutations in RNaseH2 deficient strains, whereas depletion Srs2 had no aggravating effect. This evidence confirmed that researchers Srs2 EXO1 and acted together to avoid mutations in cells deficient RNaseH2.

Analysis by Yale colleagues later confirmed, action linked between Srs2 and EXO1 showing how Srs2 EXO1 stimulated to act on the yeast DNA, allowing cleavage and repair RNMP lesions.

Dr. Potenski said its latest studies of Srs2, EXO1 RNaseH2 enzymes and should also serve as a reminder to other researchers that the known enzymes can have many roles in the life cycle of the cell, some are not yet known, and that more backup roles can be found.

Dr. Potenski said the team next plans to investigate what other biological factors can influence EXO1 as a third repair mechanism possible backup, and to study the factors that could trigger RNaseH2 mutations most likely to lead to cancer.