scholarly journals Preferred WMSA catalytic mechanism of the nucleotidyl transfer reaction in human DNA polymerase κ elucidates error-free bypass of a bulky DNA lesion

2012 ◽  
Vol 40 (18) ◽  
pp. 9193-9205 ◽  
Author(s):  
Lee Lior-Hoffmann ◽  
Lihua Wang ◽  
Shenglong Wang ◽  
Nicholas E. Geacintov ◽  
Suse Broyde ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Transfer Reaction ◽  
Catalytic Mechanism ◽  
Dna Lesion ◽  
Human Dna

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 Preferential Incorporation of G Opposite Template T by the Low-Fidelity Human DNA Polymerase ι

2000 ◽  
Vol 20 (19) ◽  
pp. 7099-7108 ◽  
Author(s):  
Yanbin Zhang ◽  
Fenghua Yuan ◽  
Xiaohua Wu ◽  
Zhigang Wang
Keyword(s):  
Dna Synthesis ◽  
Dna Polymerase ◽  
Polymerase Activity ◽  
Abasic Site ◽  
Base Pairing ◽  
Base Pairs ◽  
Dna Lesion ◽  
Biological Source ◽  
Human Dna ◽  
Base Selection

ABSTRACT DNA polymerase activity is essential for replication, recombination, repair, and mutagenesis. All DNA polymerases studied so far from any biological source synthesize DNA by the Watson-Crick base-pairing rule, incorporating A, G, C, and T opposite the templates T, C, G, and A, respectively. Non-Watson-Crick base pairs would lead to mutations. In this report, we describe the ninth human DNA polymerase, Polι, encoded by the RAD30B gene. We show that human Polι violates the Watson-Crick base-pairing rule opposite template T. During base selection, human Polι preferred T-G base pairing, leading to G incorporation opposite template T. The resulting T-G base pair was less efficiently extended by human Polι compared to the Watson-Crick base pairs. Consequently, DNA synthesis frequently aborted opposite template T, a property we designated the T stop. This T stop restricted human Polι to a very short stretch of DNA synthesis. Furthermore, kinetic analyses show that human Polι copies template C with extraordinarily low fidelity, misincorporating T, A, and C with unprecedented frequencies of 1/9, 1/10, and 1/11, respectively. Human Polι incorporated one nucleotide opposite a template abasic site more efficiently than opposite a template T, suggesting a role for human Polι in DNA lesion bypass. The unique features of preferential G incorporation opposite template T and T stop suggest that DNA Polι may additionally play a specialized function in human biology.

scholarly journals Covalent Trapping of Human DNA Polymerase β by the Oxidative DNA Lesion 2-Deoxyribonolactone

2002 ◽  
Vol 277 (10) ◽  
pp. 7637-7640 ◽  
Author(s):  
Michael S. DeMott ◽  
Ergin Beyret ◽  
Donny Wong ◽  
Brian C. Bales ◽  
Jae-Taeg Hwang ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Polymerase Β ◽  
Dna Lesion ◽  
Human Dna ◽  
Covalent Trapping

scholarly journals Translesion synthesis of the major nitrogen mustard-induced DNA lesion by human DNA polymerase η

2020 ◽  
Vol 477 (23) ◽  
pp. 4543-4558
Author(s):  
Hunmin Jung ◽  
Naveen Kumar Rayala ◽  
Seongmin Lee
Keyword(s):  
Dna Polymerase ◽  
Nitrogen Mustard ◽  
Alkylating Agents ◽  
Twist Angle ◽  
Translesion Synthesis ◽  
Major Groove ◽  
Dna Lesion ◽  
Human Dna ◽  
Interstrand Cross Links ◽  
A Site

Nitrogen mustards are among the first modern anticancer chemotherapeutics that are still widely used as non-specific anticancer alkylating agents. While the mechanism of action of mustard drugs involves the generation of DNA interstrand cross-links, the predominant lesions produced by these drugs are nitrogen half-mustard-N7-dG (NHMG) adducts. The bulky major groove lesion NHMG, if left unrepaired, can be bypassed by translesion synthesis (TLS) DNA polymerases. However, studies of the TLS past NHMG have not been reported so far. Here, we present the first synthesis of an oligonucleotide containing a site-specific NHMG. We also report kinetic and structural characterization of human DNA polymerase η (polη) bypassing NHMG. The templating NHMG slows dCTP incorporation ∼130-fold, while it increases the misincorporation frequency ∼10–30-fold, highlighting the promutagenic nature of NHMG. A crystal structure of polη incorporating dCTP opposite NHMG shows a Watson–Crick NHMG:dCTP base pair with a large propeller twist angle. The nitrogen half-mustard moiety fits snugly into an open cleft created by the Arg61–Trp64 loop of polη, suggesting a role of the Arg61–Trp64 loop in accommodating bulky major groove adducts during lesion bypass. Overall, our results presented here to provide first insights into the TLS of the major DNA adduct formed by nitrogen mustard drugs.

scholarly journals Structure of Human DNA Polymerase κ Inserting dATP Opposite an 8-OxoG DNA Lesion

PLoS ONE ◽  
2009 ◽  
Vol 4 (6) ◽  
pp. e5766 ◽  
Author(s):  
Rodrigo Vasquez-Del Carpio ◽  
Timothy D. Silverstein ◽  
Samer Lone ◽  
Michael K. Swan ◽  
Jayati R. Choudhury ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Lesion ◽  
Human Dna

scholarly journals Effects of Twelve Germline Missense Variations on DNA Lesion and G-Quadruplex Bypass Activities of Human DNA Polymerase REV1

2016 ◽  
Vol 29 (3) ◽  
pp. 367-379 ◽  
Author(s):  
Mina Yeom ◽  
In-Hyeok Kim ◽  
Jae-Kwon Kim ◽  
KyeongJin Kang ◽  
Robert L. Eoff ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Dna Lesion ◽  
Human Dna ◽  
G Quadruplex

scholarly journals Catalytic mechanism of human DNA polymerase λ with Mg2+ and Mn2+ from ab initio quantum mechanical/molecular mechanical studies

DNA Repair ◽  
2008 ◽  
Vol 7 (11) ◽  
pp. 1824-1834 ◽  
Author(s):  
G. Andrés Cisneros ◽  
Lalith Perera ◽  
Miguel García-Díaz ◽  
Katarzyna Bebenek ◽  
Thomas A. Kunkel ◽  
...  
Keyword(s):  
Ab Initio ◽  
Dna Polymerase ◽  
Catalytic Mechanism ◽  
Quantum Mechanical ◽  
Human Dna ◽  
Dna Polymerase Λ ◽  
Mechanical Studies
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