Variation in G-quadruplex sequence and topology differentially impacts human DNA polymerase fidelity

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F22%3A00564038" target="_blank" >RIV/68081707:_____/22:00564038 - isvavai.cz</a>

Result on the web

<a href="https://www.sciencedirect.com/science/article/pii/S1568786422001355?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S1568786422001355?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.dnarep.2022.103402" target="_blank" >10.1016/j.dnarep.2022.103402</a>

Result language

angličtina

Original language name

Variation in G-quadruplex sequence and topology differentially impacts human DNA polymerase fidelity

Original language description

G-quadruplexes (G4s), a type of non-B DNA, play important roles in a wide range of molecular processes, including replication, transcription, and translation. Genome integrity relies on efficient and accurate DNA synthesis, and is compromised by various stressors, to which non-B DNA structures such as G4s can be partic-ularly vulnerable. However, the impact of G4 structures on DNA polymerase fidelity is largely unknown. Using an in vitro forward mutation assay, we investigated the fidelity of human DNA polymerases delta (delta 4, foursubunit), eta (eta), and kappa (kappa) during synthesis of G4 motifs representing those in the human genome. The motifs differ in sequence, topology, and stability, features that may affect DNA polymerase errors. Polymerase error rate hierarchy (delta 4 < kappa < eta) is largely maintained during G4 synthesis. Importantly, we observed unique polymerase error signatures during synthesis of VEGF G4 motifs, stable G4s which form parallel topologies. These statistically significant errors occurred within, immediately flanking, and encompassing the G4 motif. For pol delta 4, the errors were deletions, insertions and complex errors within the G4 or encompassing the G4 motif and surrounding sequence. For pol eta, the errors occurred in 3' sequences flanking the G4 motif. For pol kappa, the errors were frameshift mutations within G-tracts of the G4. Because these error signatures were not observed during synthesis of an antiparallel G4 and, to a lesser extent, a hybrid G4, we suggest that G4 topology and/or stability could influence polymerase fidelity. Using in silico analyses, we show that most polymerase errors are predicted to have minimal effects on predicted G4 stability. Our results provide a unique view of G4s not previously elucidated, showing that G4 motif heterogeneity differentially influences polymerase fidelity within the motif and flanking sequences. Thus, our study advances the understanding of how DNA polymerase errors contribute to G4 mutagenesis.

Czech name

—

Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10603 - Genetics and heredity (medical genetics to be 3)

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2022

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Dna Repair

ISSN

1568-7864

e-ISSN

1568-7856

Volume of the periodical

119

Issue of the periodical within the volume

NOV 2022

Country of publishing house

NL - THE KINGDOM OF THE NETHERLANDS

Number of pages

12

Pages from-to

103402

UT code for WoS article

000876367300004

EID of the result in the Scopus database

2-s2.0-85138035194