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Impaired base excision repair is related to the pathogenesis of non-alcoholic fatty liver disease

100%

Ziółkowska S., Czarny P., Szemraj J.

Acta Universitatis Lodziensis. Folia Biologica et Oecologica

2020

vol. 16

5-11

Non-alcoholic fatty disease (NAFLD) is a liver disorder that affects up to 30% of the population, mainly in Western countries. It is estimated that up to 75% of NAFLD patients will develop a more aggressive form of the disease, non-alcoholic steatohepatitis (NASH). NAFLD can lead to fibrosis and liver failure; however, it is difficult to diagnose NAFLD due to its non-specific symptoms. Unfortunately, there is no treatment available for this disease. The risk factors of NAFLD are obesity and insulin resistance (IR). The molecular factors that seem to play an important role in the pathogenesis of NAFLD are oxidative stress as well as impaired DNA damage repair processes; a great body of evidence confirms an association with the base excision repair (BER) pathway. The activity of BER is decreased in patients with NAFLD and in animal models of this disease. In order to better understand the underlying basis of the disease, knowledge should be broadened in the area of DNA repair in NAFLD.

Mismatch dependent uracil/thymine-DNA glycosylases excise exocyclic hydroxyethano and hydroxypropano cytosine adducts.

88%

Borys-Brzywczy E., Arczewska K. D., Saparbaev M., Hardeland U., Schär P., Kuśmierek J. T.

Acta Biochimica Polonica

2005

vol. 52

issue 1

149-165

Exocyclic adducts of DNA bases, such as etheno- and hydroxyalkano- ones, are generated by a variety of bifunctional agents, including endogenously formed products of lipid peroxidation. In this work we selectively modified cytosines in the 5'-d(TTT TTT CTT TTT CTT TTT CTT TTT T)-3' oligonucleotide using: chloroacetaldehyde to obtain 3,N4-α-hydroxyethano- (HEC) and 3,N4-etheno- (εC), acrolein to obtain 3,N4-α-hydroxypropano- (HPC) and crotonaldehyde to obtain 3,N4-α-hydroxy-γ-methylpropano- (mHPC) adducts of cytosine. The studied adducts are alkali-labile which results in oligonucleotide strain breaks at the sites of modification upon strong base treatment. The oligonucleotides carrying adducted cytosines were studied as substrates of Escherichia coli Mug, human TDG and fission yeast Thp1p glycosylases. All the adducts studied are excised by bacterial Mug although with various efficiency: εC >HEC >HPC >mHPC. The yeast enzyme excises efficiently εC ł HEC >HPC, whereas the human enzyme excises only εC. The pH-dependence curves of excision of εC, HEC and HPC by Mug are bell shaped and the most efficient excision of adducts occurs within the pH range of 8.6-9.6. The observed increase of excision of HEC and HPC above pH 7.2 can be explained by deprotonation of these adducts, which are high pKa compounds and exist in a protonated form at neutrality. On the other hand, since εC is in a neutral form in the pH range studied, we postulate an involvement of an additional catalytic factor. We hypothesize that the enzyme structure undergoes a pH-induced rearrangement allowing the participation of Lys68 of Mug in catalysis via a hydrogen bond interaction of its ε-amino group with N4 of the cytosine exocyclic adducts.

Poly(ADP-ribose) polymerase in base excision repair: always engaged, but not essential for DNA damage processing.

75%

Allinson S. L., Dianova I. I., Dianov G. L.

Acta Biochimica Polonica

2003

vol. 50

issue 1

169-179

Poly(ADP-ribose) polymerase (PARP-1) is an abundant nuclear protein with a high affinity for single- and double-strand DNA breaks. Its binding to strand breaks promotes catalysis of the covalent modification of nuclear proteins with poly(ADP-ribose) synthesised from NAD+. PARP-1-knockout cells are extremely sensitive to alkylating agents, suggesting the involvement of PARP-1 in base excision repair; however, its role remains unclear. We investigated the dependence of base excision repair pathways on PARP-1 and NAD+ using whole cell extracts derived from normal and PARP-1 deficient mouse cells and DNA substrates containing abasic sites. In normal extracts the rate of repair was highly dependent on NAD+. We found that in the absence of NAD+ repair was slowed down 4-6-fold after incision of the abasic site. We also established that in extracts from PARP-1 deficient mouse cells, repair of both regular and reduced abasic sites was increased with respect to normal extracts and was NAD+-independent, suggesting that in both short- and long-patch BER PARP-1 slows down, rather than stimulates, the repair reaction. Our data support the proposal that PARP-1 does not play a major role in catalysis of DNA damage processing via either base excision repair pathway.

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2 Acta Biochimica Polonica

1 Acta Universitatis Lodziensis. Folia Biologica et Oecologica

1 2020

1 2005

1 2003

1 Allinson S. L.

1 Arczewska K. D.

1 Borys-Brzywczy E.

1 Czarny P.

1 Dianov G. L.

1 Dianova I. I.

1 Hardeland U.

1 Kuśmierek J. T.

1 Saparbaev M.

1 Schär P.

1 Szemraj J.

1 Ziółkowska S.

Search results

Impaired base excision repair is related to the pathogenesis of non-alcoholic fatty liver disease

Mismatch dependent uracil/thymine-DNA glycosylases excise exocyclic hydroxyethano and hydroxypropano cytosine adducts.

Poly(ADP-ribose) polymerase in base excision repair: always engaged, but not essential for DNA damage processing.