Replicative DNA polymerase epsilon and delta holoenzymes show wide-ranging inhibition at G-quadruplexes in the human genome

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68081707%3A_____%2F25%3A00619610" target="_blank" >RIV/68081707:_____/25:00619610 - isvavai.cz</a>

Result on the web

<a href="https://academic.oup.com/nar/article/53/8/gkaf352/8121651?login=true" target="_blank" >https://academic.oup.com/nar/article/53/8/gkaf352/8121651?login=true</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/nar/gkaf352" target="_blank" >10.1093/nar/gkaf352</a>

Result language

angličtina

Original language name

Replicative DNA polymerase epsilon and delta holoenzymes show wide-ranging inhibition at G-quadruplexes in the human genome

Original language description

G-quadruplexes (G4s) are functional elements of the human genome, some of which inhibit DNA replication. We investigated replication of G4s within highly abundant microsatellite (GGGA, GGGT) and transposable element (L1 and SVA) sequences. We found that genome-wide, numerous motifs are located preferentially on the replication leading strand and the transcribed strand templates. We directly tested replicative polymerase & varepsilon, and delta holoenzyme inhibition at these G4s, compared to low abundant motifs. For all G4s, DNA synthesis inhibition was higher on the G-rich than C-rich strand or control sequence. No single G4 was an absolute block for either holoenzyme, however, the inhibitory potential varied over an order of magnitude. Biophysical analyses showed the motifs form varying topologies, but replicative polymerase inhibition did not correlate with a specific G4 structure. Addition of the G4 stabilizer pyridostatin severely inhibited forward polymerase synthesis specifically on the G-rich strand, enhancing G/C strand asynchrony. Our results reveal that replicative polymerase inhibition at every G4 examined is distinct, causing complementary strand synthesis to become asynchronous, which could contribute to slowed fork elongation. Altogether, we provide critical information regarding how replicative eukaryotic holoenzymes navigate synthesis through G4s naturally occurring thousands of times in functional regions of the human genome.

Czech name

—

Czech description

—

Type

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

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GA21-00580S" target="_blank" >GA21-00580S: How plant transposable elements contribute to the genomic landscape and organization of interphase nucleus</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2025

Confidentiality

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

Name of the periodical

Nucleic Acids Research

ISSN

0305-1048

e-ISSN

1362-4962

Volume of the periodical

53

Issue of the periodical within the volume

8

Country of publishing house

GB - UNITED KINGDOM

Number of pages

23

Pages from-to

gkaf352

UT code for WoS article

001478101200001

EID of the result in the Scopus database

2-s2.0-105004043451