The recognition of the Swedish went this year to Tomas Lindahl, Paul Modrich and Aziz Sancar, three pioneers in the study of different molecular mechanisms that allow you to repair the damages that can undergo DNA
Tomas Lindahl , born in Stockholm, Sweden, in 1938, is currently affiliated with the Francis Crick Institute in Hertfordshire, UK.
Paul Modrich , born in 1946, is currently affiliated with the Howard Hughes Medical Institute, Durham, North Carolina, United States.
Aziz Sancar was born in 1946 in Savur in Turkey, and he is currently affiliated with the University of North Carolina at Chapel Hill, United States.
The DNA molecule is present in all cells of a living organism and that encodes information critical to the its operation. A single strand of DNA is formed by a long sequence of nucleotides that differ between them for a part of them, named nitrogenous base, which may be of four types: adenine (A), cytosine (C), guanine (G) and thymine (T). For this reason it is often said that the entire code of life is written with only four letters: A, C, G and T.
A coding system so complex is exposed constantly to the risk of damage, both by chemical and physical agents both for environmental effect of physiological mechanisms that undergo errors. Some of these damages remain in the gene pool without giving any major problems, while others lead to instability of the DNA molecule and make it impossible for the expression of specific genes, causing diseases such as cancer or neurodegenerative diseases.
‘But evolution has endowed all living beings of an efficient system of “repair” of the DNA that reduces errors to an acceptable level. The first repair mechanism
discovered historically derived from research on photoreactivation, he studied since the twenties of the twentieth century, well before it was identified DNA, in 1953, as a molecule that encodes genetic information. In summary, the photoreactivation is the resumption of normal cellular activities, induced by lighting with visible light in a cell after it has been damaged and broken by X-ray or ultraviolet light.
It was the Italian Renato Dulbecco, Nobel Prize for medicine or physiologists in 1975, to find in a search of 1950 that the basis of photoreactivation there is a mechanism enzyme whose activity depends on the light. The enzyme in question, found in the following years, is called fotolitasi.
In the sixties it was able to show that the effect on DNA irradiation with ultraviolet rays is the introduction of thymine dimers, ie, the union between two thymine residues on the same side of the double helix of DNA. Visible light instead activates the molecular mechanism that allows the excision, ie deletion, then called nucleotide excision repair (nucleotide excision repair, NER).
The Nobel Prize for chemistry was Aziz Sancar awarded for his contributions to the characterization of this complex machinery of DNA repair. In 1978, while still a student, Sancar managed to clone the gene of the bacterium Escherichia coli for fotolitasi and amplify the product in vivo, featuring for the first time the enzyme. Later, he invented a method to identify proteins involved in the process, reconstructing all the essential steps of the nucleotide excision repair, illustrated in a study published in 1983. In the years between 1984 and 1989, demonstrated that Sancar fotolitasi can convert light energy into chemical energy, which is necessary to trigger the removal of thymine dimers from DNA.
Understanding how DNA is damaged by a physical agent is a key step. But we must also consider that the DNA has a limited chemical stability even in the absence of external physical-chemical agents, as shown by the research of the second award this year, Tomas Lindahl.
Under physiological conditions, the DNA is in fact subject to a series of chemical reactions capable of modifying the bases of DNA and thereby to increase the risk of harmful mutations. Lindahl in particular has shown that in a process called depurination nucleotides can spontaneously lose the nitrogenous bases adenine and guanine, called purines. Another fundamental discovery of Lindahl is that, again in physiological conditions, in the DNA there is a relatively high rate of the process of deamination of cytosine, in which this nitrogenous base loses the amino group, transforming into uracil (the nitrogenous base which replaces thymine in RNA).
Starting from the premise that an injury so common DNA had to have some mechanism of repair, Lindahl arrived at the discovery of the protein uracil-DNA glycosylase (UNG) and 3-methyladenine glycosylase , now known to be part of a machine known as base excision repair (base excision repair, BER).
The DNA and the molecular mechanisms that allow replication are an extraordinary machine to store information necessary for life and for its transmission to the offspring. Cell division is, however, a delicate step, which must be duplicated in about three billion bases; therefore some error inevitably occurs. When mistakes lead to failure of the coupling formation of the bases – A couples only with T and C with G only – we talk about mismatched (mismatch).
Even for pairing is incorrect un’apposito molecular machinery repair, the operation of which has been clarified thanks to research by Paul Modrich, the third of the winners this year. In 1983, Modrich showed that a key step of the repair of the mismatches is methylation, namely the bond of a methyl group, to the bases of the DNA. Years of research led Modrich to demonstrate that the process of repair depends on the ATP, the molecule that is also a source of energy used in many processes that take place in the cell, and, in 1989, to rebuild the entire repair process in vitro, with the definition of many of the molecules involved. Over two thousand years, finally, the research Modrich have expanded the mechanisms of DNA repair in eukaryotic cells, with important results.
Tomas Lindah l was born in Stockholm, Sweden, in 1938, he received his PhD at the Karolinska Institute in the same city, and a doctorate in medicine in 1970. He made his first studies at Princeton University and then at the Rockefeller University. It was established after the United Kingdom, continued his academic career at the Cancer Research UK since 1981.
Paul Modrich , born in Raton, United States, 1946 , received his PhD in 1973.
Aziz Sancar was born in 1946 in Savur, Turkey. After graduating from the University of Istanbul, he received his PhD at the University of Dallas, Texas.
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