Why is DNA vital to survival
Damage to the genetic material: DNA repair is vital, but undesirable in cancer cells
Specialized repair mechanisms exist for the different types of DNA damage. Doctors want to use them now.
Deoxyribonucleic acid is chemically fairly stable and this is probably one of the reasons why it has established itself as the carrier of the gene code. The genetic information is correctly mapped over thousands of cell division generations. However, such a molecule is also susceptible to damage. It is imperative that these be remedied, otherwise there is a risk of faulty base pairings - mutations - which can make you chronically ill or even fatal. There are numerous diseases the etiology of which remained unexplained until one understood how DNA repair works and what the effects of the defects are.
Uracil does not belong in the DNA
Oncology is now trying to overcome malignancies by paralyzing such repair mechanisms. The tumor can then no longer repair the DNA damage after chemotherapy. Three biochemists, Tomas Lindahl, Paul Modrich and Aziz Sancar, spent decades researching how cells repair DNA single strands. The 2015 Nobel Prize for Chemistry went to these laureates not least because their basic research was so important for medicine.
For example, cytosine often loses an amino group, then suddenly uracil is found in the DNA - where it doesn't belong. Because uracil pairs with adenine instead of guanine, the actual partner of cytosine. Lindahl predicted a repair mechanism for this cause of mutations early on. In 1974 he reported on his discovery of uracil DNA glycosylase (UNG), an enzyme that can cut out misplaced uracil from the DNA strand (graphic). He was the first to describe the previously unknown base excision repair (BER).
Since Lindahl's groundbreaking discovery, a number of other DNA glycosylases have been found in addition to the UNG that cut out modified bases in a targeted manner. Because of this diversity of enzymes, BER is one of the most important, versatile and evolutionarily oldest DNA repair mechanisms.
Before cells can divide, the genetic information has to be doubled, in humans this is 3.3 billion base pairs. About 2 out of a million base pairs are wrong in the newly synthesized DNA - they do not match the opposite, there is a DNA mismatch that must be repaired as quickly as possible. Otherwise the daughter cells “inherit” the error. But how do repair enzymes know which base is right, which base is wrong, and how do they work?
The country doctor and the DNA
In the early 1980s, Paul Modrich and colleagues checked whether there were markers for this. In fact, the enzymes only repair DNA without methyl groups, and that is exactly what is not yet present in the freshly synthesized strand. In 1989 he succeeded in identifying the enzymes involved and in reproducing the mismatch repair (MMR) completely outside of the living cell.
A third repair mechanism, nucleotide excision repair (NER), was discovered by Aziz Sancar, who came to Texas in the 1970s as a Turkish country doctor to study molecular biology. His doctoral thesis dealt with the enzyme photolyase, which, for example, reduces radiation damage after exposure to UV. At first he was met with a lack of interest, was given no research opportunities and had to take a position as a technician at Yale in order to continue working on DNA repair.
DNA parts completely new
Sancar reconstructed how the enzymes involved in NER work. UV radiation causes DNA bases to chemically react with one another, creating dimers. The removal of a single base pair is not sufficient here. The enzymes identified by Sancar cut out entire sections of the double helix. In addition, they remove a few correct base pairs above and below the injured region, after which the section is restored because the undamaged counterpart of the double strand was retained. Sancar is currently researching how DNA repair and circadian rhythms are related.
What happens when the repair no longer works is easy to measure in bacteria: the mutation rate increases and they do not survive for long. If the control systems fail in humans, this is accompanied by extremely complex clinical pictures. Malfunction of the NER, for example, causes three rare but serious hereditary diseases: xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). More than 40 genes are currently associated with NER, and a corresponding number of syndromes are caused by mutations in these genes.
Xeroderma pigmentosum is mainly a skin disease, the sun-exposed skin areas are atrophic and have pigmentation disorders. Skin cancer is the leading cause of death, and these patients are only 40% likely to be over 20 years old. Fortunately, UV protection can significantly reduce the risk. Depending on the genetic defect, there may also be neurological-degenerative pathologies, for example if the NER is completely inoperable.
The clinical manifestations of Cockayne syndrome, on the other hand, could hardly be more different. Dramatic growth disorders occur here during the first few years of life, followed by a number of typical age-related pathologies. In Cockayne syndrome, NER function can also be affected to varying degrees. In the more severe type, it is the clinical picture of Cerebro-Oculo-Facial Syndrome (COFS); it is much milder than UV Sensitivity Syndrome (UVSS).
However, it is not understood which gene mutations are responsible for this differentiation in which way. Trichothiodystrophy is characterized by symptoms similar to Cockayne syndrome, plus brittle hair and nails. Defects in BER and MMR are associated with a predisposition to malignant diseases or other symptoms, especially neurodegenerative ones. The best researched MMR defect is Lynch Syndrome (LS), the incidence of malignancy is increased in the patients, and above all they are at risk of developing more colon carcinomas.
However, MMR and BER repair mechanisms also protect against neurodegenerative diseases such as Huntington's disease and myotonic dystrophy 1. It is still unclear to what extent this also applies to Alzheimer's dementia; It is similar with autoimmune diseases.
Many approaches for the clinic
So far there is no curative therapy for repair defects, only symptomatic measures such as UV protection for xeroderma pigmentosum. There are, however, various approaches to using these mechanisms in the future. Sancar found that NER activity depends on the circadian rhythm, the "internal clock".
The current chemotherapies do not yet take this into account, but the treatment could be carried out at the time of the lowest NER activity of the tumor cells. Before this succeeds - in order to maximally damage the tumor with minimal side effects for the healthy tissue - the dependencies on circadian rhythms have to be researched in more detail.
Another example shows the influence of MMR on the increasingly popular immunotherapies. Some cancer cells can outsmart T cells. This mechanism is dependent on the physical interaction between a T cell receptor (PD-1) and a ligand of the cancer cell (PDL-1). If an antibody blocks the PD-1 receptor, this disrupts the immune evasion. This succeeds all the more effectively, the more the MMR mechanism is disturbed in the tumor cells. In this way, the treatment can be more personalized for each patient depending on the status of the DNA repair function of the cancer cells. The BRCA1 and BRCA2 genes also play an important role in DNA repair. If the proteins encoded by these genes are not active - which is the case in many women with breast cancer or ovarian cancer - then on the one hand the genetic variant and repair dysfunction have contributed to the development of the tumors. At the same time, however, this predisposition can be used for therapy with so-called PARP inhibitors: Cancer cells in particular can no longer neutralize therapy-induced DNA damage because they lack the repair enzymes.
The work for these Nobel Prizes was published more than 25 years ago. The awards make it clear once again that the importance of basic research often only becomes apparent in retrospect and can still produce positive practical applications for a long time to come.
Ashley B. Williams, Prof. Dr. rer. nat. Bjorn Schumacher
Institute for Genome Stability in Aging and Disease, Cologne Cluster of Excellence in Cellular Stress Responses in Aging-associated Diseases (CECAD) and Center for Molecular Medicine (ZMMK), University of Cologne
Conflict of interest: Author Schumacher receives support from the German Research Foundation, the European Research Council Marie Curie, the German-Israeli Foundation, the German Cancer Aid and the Federal Ministry of Education and Research.
The contribution is not subject to the peer review process.
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