scholarly journals Characterization of DNA Substrate Binding to the Phosphatase Domain of the DNA Repair Enzyme Polynucleotide Kinase/Phosphatase

Biochemistry ◽  
2017 ◽  
Vol 56 (12) ◽  
pp. 1737-1745 ◽  
Author(s):  
Zahra Havali-Shahriari ◽  
Michael Weinfeld ◽  
J. N. Mark Glover
Keyword(s):  
Dna Repair ◽  
Substrate Binding ◽  
Repair Enzyme ◽  
Phosphatase Domain ◽  
Polynucleotide Kinase ◽  
Dna Substrate

scholarly journals Mechanism of DNA substrate recognition by the mammalian DNA repair enzyme, Polynucleotide Kinase

2009 ◽  
Vol 37 (18) ◽  
pp. 6161-6173 ◽  
Author(s):  
N. K. Bernstein ◽  
M. Hammel ◽  
R. S. Mani ◽  
M. Weinfeld ◽  
M. Pelikan ◽  
...  
Keyword(s):  
Dna Repair ◽  
Substrate Recognition ◽  
Repair Enzyme ◽  
Polynucleotide Kinase ◽  
Dna Substrate

Functional characterization of the Caenorhabditis elegans DNA repair enzyme APN-1

DNA Repair ◽  
2012 ◽  
Vol 11 (10) ◽  
pp. 811-822 ◽  
Author(s):  
Xiaoming Yang ◽  
Jinjiang Fan ◽  
Alexander A. Ishchenko ◽  
Devang Patel ◽  
Murat K. Saparbaev ◽  
...  
Keyword(s):  
Dna Repair ◽  
Caenorhabditis Elegans ◽  
Functional Characterization ◽  
Repair Enzyme

scholarly journals Mutational survivorship bias: The case of PNKP

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0237682
Author(s):  
Luis Bermúdez-Guzmán ◽  
Gabriel Jimenez-Huezo ◽  
Andrés Arguedas ◽  
Alejandro Leal
Keyword(s):  
Dna Repair ◽  
Kinase Domain ◽  
Multidomain Proteins ◽  
Repair Enzyme ◽  
Phosphatase Domain ◽  
Future Studies ◽  
Mitochondrial Dna Repair ◽  
The Central Nervous System ◽  
Survivorship Bias ◽  
And Function

The molecular function of a protein relies on its structure. Understanding how variants alter structure and function in multidomain proteins is key to elucidate the generation of a pathological phenotype. However, one may fall into the logical bias of assessing protein damage only based on the variants that are visible (survivorship bias), which can lead to partial conclusions. This is the case of PNKP, an important nuclear and mitochondrial DNA repair enzyme with both kinase and phosphatase function. Most variants in PNKP are confined to the kinase domain, leading to a pathological spectrum of three apparently distinct clinical entities. Since proteins and domains may have a different tolerability to variation, we evaluated whether variants in PNKP are under survivorship bias. Here, we provide the evidence that supports a higher tolerance in the kinase domain even when all variants reported are deleterious. Instead, the phosphatase domain is less tolerant due to its lower variant rates, a higher degree of sequence conservation, lower dN/dS ratios, and the presence of more disease-propensity hotspots. Together, our results support previous experimental evidence that demonstrated that the phosphatase domain is functionally more necessary and relevant for DNA repair, especially in the context of the development of the central nervous system. Finally, we propose the term "Wald’s domain" for future studies analyzing the possible survivorship bias in multidomain proteins.

Replacement of non-heme Fe(II) with Cu(II) in the α-ketoglutarate dependent DNA repair enzyme AlkB: Spectroscopic characterization of the active site

2007 ◽  
Vol 101 (7) ◽  
pp. 1043-1048 ◽  
Author(s):  
Boris Bleijlevens ◽  
Tara Shivarattan ◽  
Barbara Sedgwick ◽  
Stephen E.J. Rigby ◽  
Steve J. Matthews
Keyword(s):  
Dna Repair ◽  
Active Site ◽  
Spectroscopic Characterization ◽  
Repair Enzyme

Dynamic Characterization of a DNA Repair Enzyme:  NMR Studies of [methyl-13C]Methionine-Labeled DNA Polymerase β

Biochemistry ◽  
2004 ◽  
Vol 43 (28) ◽  
pp. 8911-8922 ◽  
Author(s):  
Bidisha Bose-Basu ◽  
Eugene F. DeRose ◽  
Thomas W. Kirby ◽  
Geoffrey A. Mueller ◽  
William A. Beard ◽  
...  
Keyword(s):  
Dna Repair ◽  
Dna Polymerase ◽  
Dynamic Characterization ◽  
Dna Polymerase Β ◽  
Nmr Studies ◽  
Repair Enzyme

scholarly journals Structural characterization of the virulence factor nuclease A fromStreptococcus agalactiae

2014 ◽  
Vol 70 (11) ◽  
pp. 2937-2949 ◽  
Author(s):  
Andrea F. Moon ◽  
Philippe Gaudu ◽  
Lars C. Pedersen
Keyword(s):  
Virulence Factor ◽  
Substrate Binding ◽  
Nuclease Activity ◽  
Structure Based Drug Design ◽  
X Ray Crystallography ◽  
High Resolution Structure ◽  
Group B ◽  
Increased Activity ◽  
Dna Substrate

The group B pathogenStreptococcus agalactiaecommonly populates the human gut and urogenital tract, and is a major cause of infection-based mortality in neonatal infants and in elderly or immunocompromised adults. Nuclease A (GBS_NucA), a secreted DNA/RNA nuclease, serves as a virulence factor forS. agalactiae, facilitating bacterial evasion of the human innate immune response. GBS_NucA efficiently degrades the DNA matrix component of neutrophil extracellular traps (NETs), which attempt to kill and clear invading bacteria during the early stages of infection. In order to better understand the mechanisms of DNA substrate binding and catalysis of GBS_NucA, the high-resolution structure of a catalytically inactive mutant (H148G) was solved by X-ray crystallography. Several mutants on the surface of GBS_NucA which might influence DNA substrate binding and catalysis were generated and evaluated using an imidazole chemical rescue technique. While several of these mutants severely inhibited nuclease activity, two mutants (K146R and Q183A) exhibited significantly increased activity. These structural and biochemical studies have greatly increased our understanding of the mechanism of action of GBS_NucA in bacterial virulence and may serve as a foundation for the structure-based drug design of antibacterial compounds targeted toS. agalactiae.

Characterization of Nucleobase−Amino Acid Stacking Interactions Utilized by a DNA Repair Enzyme

2006 ◽  
Vol 110 (39) ◽  
pp. 19652-19663 ◽  
Author(s):  
Lesley R. Rutledge ◽  
Lachlan S. Campbell-Verduyn ◽  
Ken C. Hunter ◽  
Stacey D. Wetmore
Keyword(s):  
Dna Repair ◽  
Amino Acid ◽  
Stacking Interactions ◽  
Repair Enzyme
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