scholarly journals Transition State in DNA Polymerase β Catalysis: Rate-Limiting Chemistry Altered by Base-Pair Configuration

Biochemistry ◽  
2014 ◽  
Vol 53 (11) ◽  
pp. 1842-1848 ◽  
Author(s):  
Keriann Oertell ◽  
Brian T. Chamberlain ◽  
Yue Wu ◽  
Elena Ferri ◽  
Boris A. Kashemirov ◽  
...  
Keyword(s):  
Transition State ◽  
Dna Polymerase ◽  
Base Pair ◽  
Dna Polymerase Β ◽  
Rate Limiting

scholarly journals Effect of β,γ-CHF- and β,γ-CHCl-dGTP Halogen Atom Stereochemistry on the Transition State of DNA Polymerase β

Biochemistry ◽  
2012 ◽  
Vol 51 (43) ◽  
pp. 8491-8501 ◽  
Author(s):  
Keriann Oertell ◽  
Yue Wu ◽  
Valeria M. Zakharova ◽  
Boris A. Kashemirov ◽  
David D. Shock ◽  
...  
Keyword(s):  
Transition State ◽  
Dna Polymerase ◽  
Halogen Atom ◽  
Dna Polymerase Β

DNA Polymerase β Fidelity:  Halomethylene-Modified Leaving Groups in Pre-Steady-State Kinetic Analysis Reveal Differences at the Chemical Transition State†

Biochemistry ◽  
2008 ◽  
Vol 47 (3) ◽  
pp. 870-879 ◽  
Author(s):  
Christopher A. Sucato ◽  
Thomas G. Upton ◽  
Boris A. Kashemirov ◽  
Jorge Osuna ◽  
Keriann Oertell ◽  
...  
Keyword(s):  
Steady State ◽  
Transition State ◽  
Kinetic Analysis ◽  
Dna Polymerase ◽  
Dna Polymerase Β ◽  
Steady State Kinetic ◽  
Leaving Groups ◽  
State Kinetic

scholarly journals An Abridged Transition State Model To Derive Structure, Dynamics, and Energy Components of DNA Polymerase β Fidelity

Biochemistry ◽  
2011 ◽  
Vol 50 (32) ◽  
pp. 7023-7032 ◽  
Author(s):  
Martin Klvaňa ◽  
Petr Jeřábek ◽  
Myron F. Goodman ◽  
Jan Florián
Keyword(s):  
Transition State ◽  
Dna Polymerase ◽  
State Model ◽  
Dna Polymerase Β ◽  
Structure Dynamics ◽  
Energy Components

scholarly journals Insights into the effect of minor groove interactions and metal cofactors on mutagenic replication by human DNA polymerase β

2018 ◽  
Vol 475 (3) ◽  
pp. 571-585 ◽  
Author(s):  
Myong-Chul Koag ◽  
Seongmin Lee
Keyword(s):  
Dna Polymerase ◽  
Base Pair ◽  
Insertion Site ◽  
Kinetic Studies ◽  
Minor Groove ◽  
Dna Polymerase Β ◽  
Human Dna ◽  
Potential Factor ◽  
Enol Tautomer ◽  
Metal Cofactors

DNA polymerases accommodate various base-pair conformations in the event of incorrect insertions. In particular, Watson–Crick-like dG:dTTP base pair has been observed at the insertion site of human DNA polymerase β (pol β). A potential factor contributing to the diverse conformations of base-pair mismatches is minor groove interactions. To gain insights into the effect of minor groove interactions on base-pair conformations, we generated an Asn279Ala polβ mutant that cannot make minor groove contacts with an incoming nucleotide. We conducted structural and kinetic studies of Asn279Ala polβ in complex with incoming dTTP and templating dG or O6-methyl-dG. The crystal structure of the Asn279Ala polβ-G:T complex showed a wobble dG:dTTP base pair, indicating that the previously observed Watson–Crick-like dG:dTTP conformation was induced by the minor groove contact. In contrast, O6-methyl-dG, an analog of the enol tautomer of guanine, formed a Watson–Crick-like base pair with dTTP in the absence of the minor groove contact. These results suggest that the Watson–Crick-like G:T base pair at the insertion site is formed by the rare enol tautomers of G or T, whose population is increased by the minor groove hydrogen bond with Asn279. Kinetic studies showed that Asn279Ala mutation decreased dG:dTTP misincorporation rate six-fold in the presence of Mg2+ but increased the rate three-fold in the presence of Mn2+, highlighting the effect of minor groove interactions and metal ions on promutagenic replication by polβ.

scholarly journals Transition-state destabilization reveals how human DNA polymerase β proceeds across the chemically unstable lesion N7-methylguanine

2014 ◽  
Vol 42 (13) ◽  
pp. 8755-8766 ◽  
Author(s):  
Myong-Chul Koag ◽  
Yi Kou ◽  
Hala Ouzon-Shubeita ◽  
Seongmin Lee
Keyword(s):  
Transition State ◽  
Dna Polymerase ◽  
Dna Polymerase Β ◽  
Human Dna

scholarly journals The human checkpoint sensor and alternative DNA clamp Rad9–Rad1–Hus1 modulates the activity of DNA ligase I, a component of the long-patch base excision repair machinery

2005 ◽  
Vol 389 (1) ◽  
pp. 13-17 ◽  
Author(s):  
Ekaterina SMIRNOVA ◽  
Magali TOUEILLE ◽  
Enni MARKKANEN ◽  
Ulrich HÜBSCHER
Keyword(s):  
Quality Control ◽  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Ligase ◽  
Dna Polymerase Β ◽  
Flap Endonuclease 1 ◽  
Important Target ◽  
Dna Ligase I ◽  
Base Excision

The human checkpoint sensor and alternative clamp Rad9–Rad1–Hus1 can interact with and specifically stimulate DNA ligase I. The very recently described interactions of Rad9–Rad1–Hus1 with MutY DNA glycosylase, DNA polymerase β and Flap endonuclease 1 now complete our view that the long-patch base excision machinery is an important target of the Rad9–Rad1–Hus1 complex, thus enhancing the quality control of DNA.

scholarly journals DNA polymerase β outperforms DNA polymerase γ in key mitochondrial base excision repair activities

DNA Repair ◽  
2021 ◽  
Vol 99 ◽  
pp. 103050
Author(s):  
Beverly A. Baptiste ◽  
Stephanie L. Baringer ◽  
Tomasz Kulikowicz ◽  
Joshua A. Sommers ◽  
Deborah L. Croteau ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Base Excision Repair ◽  
Excision Repair ◽  
Dna Polymerase Β ◽  
Base Excision ◽  
Dna Polymerase Γ

scholarly journals Molecular disruption of DNA polymerase β for platinum sensitisation and synthetic lethality in epithelial ovarian cancers

Oncogene ◽  
2021 ◽  
Author(s):  
Reem Ali ◽  
Adel Alblihy ◽  
Islam M. Miligy ◽  
Muslim L. Alabdullah ◽  
Mansour Alsaleem ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Arrest ◽  
Dna Polymerase ◽  
Synthetic Lethality ◽  
Ovarian Cancer Cells ◽  
Dna Polymerase Β ◽  
Mesenchymal Transition ◽  
Platinum Sensitivity ◽  
Cycle Arrest ◽  
Ovarian Cancers

AbstractTargeting PARP1 [Poly(ADP-Ribose) Polymerase 1] for synthetic lethality is a new strategy for BRCA germ-line mutated or platinum sensitive ovarian cancers. However, not all patients respond due to intrinsic or acquired resistance to PARP1 inhibitor. Development of alternative synthetic lethality approaches is a high priority. DNA polymerase β (Polβ), a critical player in base excision repair (BER), interacts with PARP1 during DNA repair. Here we show that polβ deficiency is a predictor of platinum sensitivity in human ovarian tumours. Polβ depletion not only increased platinum sensitivity but also reduced invasion, migration and impaired EMT (epithelial to mesenchymal transition) of ovarian cancer cells. Polβ small molecular inhibitors (Pamoic acid and NSC666719) were selectively toxic to BRCA2 deficient cells and associated with double-strand breaks (DSB) accumulation, cell cycle arrest and increased apoptosis. Interestingly, PARG [Poly(ADP-Ribose) Glycohydrolase] inhibitor (PDD00017273) [but not PARP1 inhibitor (Olaparib)] was synthetically lethal in polβ deficient cells. Selective toxicity to PDD00017273 was associated with poly (ADP-ribose) accumulation, reduced nicotinamide adenine dinucleotide (NAD+) level, DSB accumulation, cell cycle arrest and increased apoptosis. In human tumours, polβ-PARG co-expression adversely impacted survival in patients. Our data provide evidence that polβ targeting is a novel strategy and warrants further pharmaceutical development in epithelial ovarian cancers.

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