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Różne twarze naprawy DNA - Nobel 2015 w dziedzinie chemii

100%

Tudek B.

Kosmos

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2016

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vol. 65

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issue 3

309-322

PL

W 2015 r. Nagroda Nobla w dziedzinie chemii została przyznana za badania mechanistyczne nad naprawą DNA Paulowi Modrichowi, Tomasowi Lindahlowi i Azizowi Sancarowi. Paul Modrich pracuje w Howard Hughes Medical Institute oraz Duke University School of Medicine, Durham, USA. Nagrodą zostały wyróżnione jego prace nad naprawą źle dopasowanych zasad, które powstają głównie podczas replikacji, zaś ten typ naprawy jest "pierwszą linią ochrony" stabilności genomu. Tomas Lindahl jest profesorem chemii medycznej i fizycznej, emerytowanym dyrektorem Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, Wielka Brytania. Nagrodę Nobla otrzymał za odkrycia w dziedzinie naprawy przez wycięcie zasady usuwającej z DNA niewielkie uszkodzenia, głównie oksydacyjne i alkilacyjne. Aziz Sancar jest profesorem biochemii i biofizyki na University of North Carolina School of Medicine, Chapel Hill, USA. Nagrodę Nobla otrzymał za osiągnięcia w dziedzinie naprawy przez wycięcie nukleotydu. System ten usuwa z DNA duże modyfikacje takie jak dimery pirymidynowe indukowane światłem ultrafioletowym. Badania uczonych stworzyły podwaliny pod zrozumienie mechanizmu ewolucji świata ożywionego, a także procesów nowotworowych i opracowanie nowoczesnych terapii.

EN

The Nobel Prize in chemistry for 2015 was awarded to Paul Modrich, Tomas Lindahl and Aziz Sancar for mechanistic studies on DNA repair. Paul Modrich works in Howard Hughes Medical Institute and Duke University School of Medicine, Durham, USA. The prize has been awarded for his work on Mismatch Repair, which removes mismatched nucleotides formed mainly during replication and is the "first line of defense" of genome stability. Tomas Lindahl is a professor of medical and physical chemistry, emeritus director of Cancer Research UK London Research Institute, Clare Hall Laboratories, South Mimms, United Kingdom. The Nobel Prize was awarded to him for discoveries on Base Excision Repair, which removes from the DNA small lesions, mainly alkylated and oxidatively formed damages. Aziz Sancar is a professor in biochemistry and biophysics at University of North Carolina School of Medicine, Chapel Hill, USA. He was awarded for the achievements on Nucleotide Excision Repair. The system removes from the DNA big lesions, such as pyrimidine dimers induced by ultraviolet light. Studies of these researchers made a basis for understanding of the evolution of living world as well as carcinogenic process and for elaboration of novel therapies.

2

Bacterial DNA repair genes and their eukaryotic homologues: 4. The role of nucleotide excision DNA repair (NER) system in mammalian cells

51%

Maddukuri L., Dudzińska D., Tudek B.

Acta Biochimica Polonica

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2007

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vol. 54

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issue 3

469-482

EN

The eukaryotic cell encounters more than one million various kinds of DNA lesions per day. The nucleotide excision repair (NER) pathway is one of the most important repair mechanisms that removes a wide spectrum of different DNA lesions. NER operates through two sub pathways: global genome repair (GGR) and transcription-coupled repair (TCR). GGR repairs the DNA damage throughout the entire genome and is initiated by the HR23B/XPC complex, while the CSB protein-governed TCR process removes DNA lesions from the actively transcribed strand. The sequence of events and the role of particular NER proteins are currently being extensively discussed. NER proteins also participate in other cellular processes like replication, transcription, chromatin maintenance and protein turnover. Defects in NER underlay severe genetic disorders: xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD).

3

Sequence-specific p53 gene damage by chloroacetaldehyde and its repair kinetics in Escherichia coli

45%

Kowalczyk P., Cieśla J. M., Saparbaev M., Laval J., Tudek B.

Acta Biochimica Polonica

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2006

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vol. 53

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issue 2

337-347

EN

Oxidative stress and certain environmental carcinogens, e.g. vinyl chloride and its metabolite chloroacetaldehyde (CAA), introduce promutagenic exocyclic adducts into DNA, among them 1,N6-ethenoadenine (εA), 3,N4-ethenocytosine (εC) and N2,3-ethenoguanine (εG). We studied sequence-specific interaction of the vinyl-chloride metabolite CAA with human p53 gene exons 5-8, using DNA Polymerase Fingerprint Analysis (DPFA), and identified sites of the highest sensitivity. CAA-induced DNA damage was more extensive in p53 regions which revealed secondary structure perturbations, and were localized in regions of mutation hot-spots. These perturbations inhibited DNA synthesis on undamaged template. We also studied the repair kinetics of CAA-induced DNA lesions in E. coli at nucleotide resolution level. A plasmid bearing full length cDNA of human p53 gene was modified in vitro with 360 mM CAA and transformed into E. coli DH5α strain, in which the adaptive response system had been induced by MMS treatment before the cells were made competent. Following transformation, plasmids were re-isolated from transformed cultures 35, 40, 50 min and 1-24 h after transformation, and further subjected to LM-PCR, using ANPG, MUG and Fpg glycosylases to identify the sites of DNA damage. In adaptive response-induced E. coli cells the majority of DNA lesions recognized by ANPG glycosylase were removed from plasmid DNA within 35 min, while MUG glycosylase excised base modifications only within 50 min, both in a sequence-dependent manner. In non-adapted cells resolution of plasmid topological forms was perturbed, suggesting inhibition of one or more bacterial topoisomerases by unrepaired ε-adducts. We also observed delayed consequences of DNA modification with CAA, manifesting as secondary DNA breaks, which appeared 3 h after transformation of damaged DNA into E. coli, and were repaired after 24 h.

4

Mutagenic specificity of imidazole ring-opened 7-methylpurines in m13mp18 phage DNA

39%

Tudek B., Grąziewicz M., Kazanova O., Zastawny T. H., Obtułowicz T., Laval J.

Acta Biochimica Polonica

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1999

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vol. 46

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issue 3

785-799

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Inhibition of DNA repair glycosylases by base analogs and tryptophan pyrolysate, Trp-P-1.

39%

Speina E., Cieśla J. M., Grąziewicz M.-A., Laval J., Kazimierczuk Z., Tudek B.

Acta Biochimica Polonica

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2005

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vol. 52

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issue 1

167-178

EN

DNA base analogs, 2,4,5,6-substituted pyrimidines and 2,6-substituted purines were tested as potential inhibitors of E. coli Fpg protein (formamidopyrimidine -DNA glycosylase). Three of the seventeen compounds tested revealed inhibitory properties. 2-Thioxanthine was the most efficient, inhibiting 50% of 2,6-diamino-4-hydroxy-5N-methyl-formamidopyrimidine (Fapy-7MeG) excision activity at 17.1 μM concentration. The measured Kgi was 4.44 ± 0.15 μM. Inhibition was observed only when the Fpg protein was first challenged to its substrate followed by the addition of the base analog, suggesting uncompetitive (catalytic) inhibition. For two other compounds, 2-thio- or 2-oxo-4,5,6-substituted pyrimidines, IC50 was only 343.3 ± 58.6 and 350 ± 24.4 μM, respectively. No change of the Fpg glycosylase activity was detected in the presence of Fapy-7MeG, up to 5 μM. We also investigated the effect of DNA structure modified by tryptophan pyrolysate (Trp-P-1) on the activity of base excision repair enzymes: Escherichia coli and human DNA glycosylases of oxidized (Fpg, Nth) and alkylated bases (TagA, AlkA, and ANPG), and for bacterial AP endonuclease (Xth protein). Trp-P-1, which changes the secondary DNA structure into non-B, non-Z most efficiently inhibited excision of alkylated bases by the AlkA glycosylase (IC50 = 1 μM). The ANPG, TagA, and Fpg proteins were also inhibited although to a lesser extent (IC50 = 76.5 μM, 96 μM, and 187.5 μM, respectively). Trp-P-1 also inhibited incision of DNA at abasic sites by the β-lyase activity of the Fpg and Nth proteins, and to a lesser extent by the Xth AP endonuclease. Thus, DNA conformation is critical for excision of damaged bases and incision of abasic sites by DNA repair enzymes.

6

Induction of aberrant crypts in the colons of rats by alkylating agents

39%

Bilbin M., Tudek B., Czeczot H.

Acta Biochimica Polonica

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1992

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vol. 39

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issue 1

113-117

7

Oxidative damage to DNA and antioxidant status in aging and age-related diseases

33%

Olinski R., Siomek A., Rozalski R., Gackowski D., Foksinski M., Guz J., Dziaman T., Szpila A., Tudek B.

Acta Biochimica Polonica

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2007

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vol. 54

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issue 1

11-26

EN

Aging is a complex process involving morphologic and biochemical changes in single cells and in the whole organism. One of the most popular explanations of how aging occurs at the molecular level is the oxidative stress hypothesis. Oxidative stress leads in many cases to an age-dependent increase in the cellular level of oxidatively modified macromolecules including DNA, and it is this increase which has been linked to various pathological conditions, such as aging, carcinogenesis, neurodegenerative and cardiovascular diseases. It is, however, possible that a number of short-comings associated with gaps in our knowledge may be responsible for the failure to produce definite results when applied to understanding the role of DNA damage in aging and age-related diseases.

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Różne twarze naprawy DNA - Nobel 2015 w dziedzinie chemii

Bacterial DNA repair genes and their eukaryotic homologues: 4. The role of nucleotide excision DNA repair (NER) system in mammalian cells

Sequence-specific p53 gene damage by chloroacetaldehyde and its repair kinetics in Escherichia coli

Mutagenic specificity of imidazole ring-opened 7-methylpurines in m13mp18 phage DNA

Inhibition of DNA repair glycosylases by base analogs and tryptophan pyrolysate, Trp-P-1.

Induction of aberrant crypts in the colons of rats by alkylating agents

Oxidative damage to DNA and antioxidant status in aging and age-related diseases