scholarly journals Effects of Active Site Mutations on Specificity of Nucleobase Binding in Human DNA Polymerase η

2016 ◽  
Vol 121 (15) ◽  
pp. 3667-3675 ◽  
Author(s):  
Melek N. Ucisik ◽  
Sharon Hammes-Schiffer
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Human Dna ◽  
Active Site Mutations

Roles of the active site residues and metal cofactors in noncanonical base-pairing during catalysis by human DNA polymerase iota

DNA Repair ◽  
2014 ◽  
Vol 22 ◽  
pp. 67-76 ◽  
Author(s):  
Alena V. Makarova ◽  
Artem Ignatov ◽  
Nataliya Miropolskaya ◽  
Andrey Kulbachinskiy
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Active Site Residues ◽  
Base Pairing ◽  
Dna Polymerase Iota ◽  
Human Dna ◽  
Metal Cofactors

scholarly journals Active Site Mutations in Mammalian DNA Polymerase δ Alter Accuracy and Replication Fork Progression

2010 ◽  
Vol 285 (42) ◽  
pp. 32264-32272 ◽  
Author(s):  
Michael W. Schmitt ◽  
Ranga N. Venkatesan ◽  
Marie-Jeanne Pillaire ◽  
Jean-Sébastien Hoffmann ◽  
Julia M. Sidorova ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Replication Fork ◽  
Dna Polymerase Δ ◽  
Replication Fork Progression ◽  
Active Site Mutations

scholarly journals Structural insights into the promutagenic bypass of the major cisplatin-induced DNA lesion

2020 ◽  
Vol 477 (5) ◽  
pp. 937-951
Author(s):  
Hala Ouzon-Shubeita ◽  
Caroline K. Vilas ◽  
Seongmin Lee
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Cisplatin Resistance ◽  
Structural Basis ◽  
Abasic Site ◽  
Dna Polymerase Β ◽  
Dna Lesion ◽  
Human Dna ◽  
Optimal Conformation ◽  
Structural Insights

The cisplatin-1,2-d(GpG) (Pt-GG) intrastrand cross-link is the predominant DNA lesion generated by cisplatin. Cisplatin has been shown to predominantly induce G to T mutations and Pt-GG permits significant misincorporation of dATP by human DNA polymerase β (polβ). In agreement, polβ overexpression, which is frequently observed in cancer cells, is linked to cisplatin resistance and a mutator phenotype. However, the structural basis for the misincorporation of dATP opposite Pt-GG is unknown. Here, we report the first structures of a DNA polymerase inaccurately bypassing Pt-GG. We solved two structures of polβ misincorporating dATP opposite the 5′-dG of Pt-GG in the presence of Mg2+ or Mn2+. The Mg2+-bound structure exhibits a sub-optimal conformation for catalysis, while the Mn2+-bound structure is in a catalytically more favorable semi-closed conformation. In both structures, dATP does not form a coplanar base pairing with Pt-GG. In the polβ active site, the syn-dATP opposite Pt-GG appears to be stabilized by protein templating and pi stacking interactions, which resembles the polβ-mediated dATP incorporation opposite an abasic site. Overall, our results suggest that the templating Pt-GG in the polβ active site behaves like an abasic site, promoting the insertion of dATP in a non-instructional manner.

scholarly journals Structural basis of DNA synthesis opposite 8-oxoguanine by human PrimPol primase-polymerase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Olga Rechkoblit ◽  
Robert E. Johnson ◽  
Yogesh K. Gupta ◽  
Louise Prakash ◽  
Satya Prakash ◽  
...  
Keyword(s):  
Dna Synthesis ◽  
Dna Polymerase ◽  
Thermodynamic Stability ◽  
Active Site ◽  
Base Pair ◽  
Translesion Synthesis ◽  
Human Cells ◽  
Structural Basis ◽  
Human Dna ◽  
Dna Template

AbstractPrimPol is a human DNA polymerase-primase that localizes to mitochondria and nucleus and bypasses the major oxidative lesion 7,8-dihydro-8-oxoguanine (oxoG) via translesion synthesis, in mostly error-free manner. We present structures of PrimPol insertion complexes with a DNA template-primer and correct dCTP or erroneous dATP opposite the lesion, as well as extension complexes with C or A as a 3′−terminal primer base. We show that during the insertion of C and extension from it, the active site is unperturbed, reflecting the readiness of PrimPol to accommodate oxoG(anti). The misinsertion of A opposite oxoG(syn) also does not alter the active site, and is likely less favorable due to lower thermodynamic stability of the oxoG(syn)•A base-pair. During the extension step, oxoG(syn) induces an opening of its base-pair with A or misalignment of the 3′-A primer terminus. Together, the structures show how PrimPol accurately synthesizes DNA opposite oxidatively damaged DNA in human cells.

scholarly journals Combining Evolutionary Conservation and Quantum Topological Analyses to Determine QM Subsystems for Biomolecular QM/MM Simulations

2021 ◽  
Author(s):  
Mark A. Hix ◽  
Emmett M. Leddin ◽  
G. Andres Cisneros
Keyword(s):  
Dna Polymerase ◽  
Active Site ◽  
Protein Sequence ◽  
Minimum Energy ◽  
Evolutionary Conservation ◽  
Structure Evolution ◽  
Minimum Energy Path ◽  
Sequence Structure ◽  
Human Dna

We present an approach that combines protein sequence/structure evolution and electron localization function (ELF) analyses. The combination of these two analysis allows the determination of whether a residue needs to be included in the QM subsystem, or can be represented by the MM environment. We have applied this approach on two systems previously investigated by QM/MM simulations, 4{oxalocrotonate tautomerase (4OT), and ten-eleven translocation-2 (TET2), that provide examples where fragments may or may not need to be included in the QM subsystem. Subsequently, we present the use of this approach to determine the appropriate QM subsystem to calculate the minimum energy path (MEP) for the reaction catalyzed by human DNA polymerase lambda? with a third cation in the active site.

scholarly journals An Incoming Nucleotide Imposes an anti to syn Conformational Change on the Templating Purine in the Human DNA Polymerase-ι Active Site

Structure ◽  
2006 ◽  
Vol 14 (4) ◽  
pp. 749-755 ◽  
Author(s):  
Deepak T. Nair ◽  
Robert E. Johnson ◽  
Louise Prakash ◽  
Satya Prakash ◽  
Aneel K. Aggarwal
Keyword(s):  
Conformational Change ◽  
Dna Polymerase ◽  
Active Site ◽  
Human Dna ◽  
Dna Polymerase Ι
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