scholarly journals Repair of Hypoxanthine in DNA Revealed by DNA Glycosylases and Endonucleases From Hyperthermophilic Archaea

2021 ◽  
Vol 12 ◽  
Author(s):  
Tan Lin ◽  
Likui Zhang ◽  
Mai Wu ◽  
Donghao Jiang ◽  
Zheng Li ◽  
...  
Keyword(s):  
Excision Repair ◽  
Dna Glycosylase ◽  
Hyperthermophilic Archaea ◽  
Future Research ◽  
Dna Glycosylases ◽  
Uracil Dna Glycosylase ◽  
Alternative Pathways ◽  
Endonuclease V ◽  
Base Excision ◽  
Dna Strand

Since hyperthermophilic Archaea (HA) thrive in high-temperature environments, which accelerate the rates of deamination of base in DNA, their genomic stability is facing a severe challenge. Hypoxanthine (Hx) is one of the common deaminated bases in DNA. Generally, replication of Hx in DNA before repaired causes AT → GC mutation. Biochemical data have demonstrated that 3-methyladenine DNA glycosylase II (AlkA) and Family V uracil DNA glycosylase (UDG) from HA could excise Hx from DNA, thus triggering a base excision repair (BER) process for Hx repair. Besides, three endonucleases have been reported from HA: Endonuclease V (EndoV), Endonuclease Q (EndoQ), and Endonuclease NucS (EndoNucS), capable of cleaving Hx-containing DNA, thereby providing alternative pathways for Hx repair. Both EndoV and EndoQ could cleave one DNA strand with Hx, thus forming a nick and further initiating an alternative excision repair (AER) process for the follow-up repair. By comparison, EndoNucS cleaves both strands of Hx-containing DNA in a restriction endonuclease manner, thus producing a double-stranded break (DSB). This created DSB might be repaired by homologous recombination (HR) or by a combination activity of DNA polymerase (DNA pol), flap endonuclease 1 (FEN1), and DNA ligase (DNA lig). Herein, we reviewed the most recent advances in repair of Hx in DNA triggered by DNA glycosylases and endonucleases from HA, and proposed future research directions.

scholarly journals Functional Analysis on a Naturally Occurring Variant of the Staphylococcus Aureus Uracil DNA Glycosylase Inhibitor

2017 ◽  
Author(s):  
Veronika Papp-Kádár ◽  
Zoltán Balázs ◽  
Gergely N. Nagy ◽  
Tünde Juhász ◽  
Károly Liliom ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Complex Formation ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Dna Glycosylases ◽  
Uracil Dna Glycosylase ◽  
Naturally Occurring ◽  
Base Excision ◽  
Interaction Surface ◽  
Uracil Base

Repair of DNA damage relies on various pathways including the base excision repair (BER) which targets erroneous bases in the DNA. Here, Uracil-DNA glycosylases (UDGs) are responsible for recognition and removal of uracil base from the DNA. Here, we characterize the interaction of Staphylococcus aureus UDG (SAUDG) with a naturally occurring variant of S. aureus uracil-DNA glycosylase inhibitor (SAUGI). This variant contains a histidine instead of a glutamate at the 24th position which affects the SAUDG:SAUGI interaction surface. We assessed the complex formation of SAUDG with these two SAUGI variants by independent biophysical methods. Our data reveal that the residue difference at the 24th position does not have a marked effect on the binding affinity, yet it confers alteration of the thermodynamics of the interaction. We propose that the E24H variant of SAUGI allows efficient complex formation, and consequently, inhibition of SAUDG.

scholarly journals SMUG2 DNA glycosylase from Pedobacter heparinus as a new subfamily of the UDG superfamily

2017 ◽  
Vol 474 (6) ◽  
pp. 923-938 ◽  
Author(s):  
Panjiao Pang ◽  
Ye Yang ◽  
Jing Li ◽  
Zhong Wang ◽  
Weiguo Cao ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Excision Repair ◽  
Phylogenetic Analyses ◽  
Dna Glycosylase ◽  
Amino Acid Residues ◽  
Uracil Dna Glycosylase ◽  
Important Amino Acid ◽  
Repair Mechanisms ◽  
Ap Sites ◽  
Base Excision

Base deamination is a common type of DNA damage that occurs in all organisms. DNA repair mechanisms are essential to maintain genome integrity, in which the base excision repair (BER) pathway plays a major role in the removal of base damage. In the BER pathway, the uracil DNA glycosylase superfamily is responsible for excising the deaminated bases from DNA and generates apurinic/apyrimidinic (AP) sites. Using bioinformatics tools, we identified a family 3 SMUG1-like DNA glycoyslase from Pedobacter heparinus (named Phe SMUG2), which displays catalytic activities towards DNA containing uracil or hypoxanthine/xanthine. Phylogenetic analyses show that SMUG2 enzymes are closely related to family 3 SMUG1s but belong to a distinct branch of the family. The high-resolution crystal structure of the apoenzyme reveals that the general fold of Phe SMUG2 resembles SMUG1s, yet with several distinct local structural differences. Mutational studies, coupled with structural modeling, identified several important amino acid residues for glycosylase activity. Substitution of G65 with a tyrosine results in loss of all glycosylase activity. The crystal structure of the G65Y mutant suggests a potential misalignment at the active site due to the mutation. The relationship between the new subfamily and other families in the UDG superfamily is discussed. The present study provides new mechanistic insight into the molecular mechanism of the UDG superfamily.

scholarly journals Uracil-DNA Glycosylase in Base Excision Repair and Adaptive Immunity

2011 ◽  
Vol 286 (19) ◽  
pp. 16669-16680 ◽  
Author(s):  
Berit Doseth ◽  
Torkild Visnes ◽  
Anders Wallenius ◽  
Ida Ericsson ◽  
Antonio Sarno ◽  
...  
Keyword(s):  
Adaptive Immunity ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase ◽  
Base Excision

scholarly journals The p53-Induced Oncogenic Phosphatase PPM1D Interacts with Uracil DNA Glycosylase and Suppresses Base Excision Repair

2004 ◽  
Vol 15 (4) ◽  
pp. 621-634 ◽  
Author(s):  
Xiongbin Lu ◽  
Dora Bocangel ◽  
Bonnie Nannenga ◽  
Hiroshi Yamaguchi ◽  
Ettore Appella ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase ◽  
Base Excision

scholarly journals Base-Excision Repair Activity of Uracil-DNA Glycosylase Monitored Using the Latch Zone of α-Hemolysin

2013 ◽  
Vol 135 (51) ◽  
pp. 19347-19353 ◽  
Author(s):  
Qian Jin ◽  
Aaron M. Fleming ◽  
Robert P. Johnson ◽  
Yun Ding ◽  
Cynthia J. Burrows ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Uracil Dna Glycosylase ◽  
Repair Activity ◽  
Base Excision

scholarly journals Deficient Uracil Base Excision Repair Leads to Persistent dUMP in HIV Proviruses During Infection of Monocytes and Macrophages

2020 ◽  
Author(s):  
Mesfin Meshesha ◽  
Alexandre Esadze ◽  
Junru Cui ◽  
Natela Churgulia ◽  
Sushil Kumar Sahu ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Reverse Transcription ◽  
Excision Repair ◽  
Dna Glycosylase ◽  
Target Cells ◽  
Viral Dna ◽  
Uracil Dna Glycosylase ◽  
Monocytes And Macrophages ◽  
Base Excision ◽  
Uracil Base

Abstract Background Non-dividing cells of the myeloid lineage such as monocytes and macrophages are target cells of HIV that have low dNTP pool concentrations and elevated levels of dUTP, which leads to frequent incorporation of dUMP opposite to A during reverse transcription (“uracilation”). One factor determining the fate of dUMP in proviral DNA is the host cell uracil base excision repair (UBER) system. Here we explore the relative UBER capacity of monocytes (MC) and monocyte-derived macrophages (MDM) and the fate of integrated uracilated viruses in both cell types to understand the implications of viral dUMP on HIV diversification and infectivity.Results We find that monocytes are almost completely devoid of functional UBER, while macrophages are mainly deficient in the initial enzyme uracil DNA glycosylase (hUNG2). Accordingly, dUMP persists in viral DNA during the lifetime of a MC and can only be removed after differentiation of MC into MDM. Overexpression of human uracil DNA glycosylase in MDM prior to infection resulted in rapid removal of dUMP from HIV cDNA and near complete depletion of dUMP-containing viral copies. This finding establishes that the low hUNG2 expression level in these cells limits UBER but that hUNG2 is restrictive against uracilated viruses. In contrast, overexpression of hUNG2 after viral integration did not accelerate the excision of uracils, suggesting that they may poorly accessible in the context of chromatin. We found that viral DNA molecules with incorporated dUMP contained unique (+) strand transversion mutations that were not observed when dUMP was absent (G→T, T→A, T→G, A→C). These observations and other considerations suggest that dUMP introduces errors predominantly during (-) strand synthesis when the template is RNA. These mutations may arise from the increased mispairing and duplex destabilizing effects of dUMP relative to dTMP during reverse transcription. Overall, the likelihood of producing a functional virus from in vitro infection of MC is about 50-fold and 300-fold reduced as compared to MDM and activated T cells.Conclusions The results implicate viral dUMP incorporation in MC and MDM as a potential viral diversification and restriction pathway during human HIV infection.

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