High speed of fork progression induces DNA replication stress and genomic instability

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F18%3A73587602" target="_blank" >RIV/61989592:15110/18:73587602 - isvavai.cz</a>

Result on the web

<a href="https://www.nature.com/articles/s41586-018-0261-5" target="_blank" >https://www.nature.com/articles/s41586-018-0261-5</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1038/s41586-018-0261-5" target="_blank" >10.1038/s41586-018-0261-5</a>

Result language

angličtina

Original language name

High speed of fork progression induces DNA replication stress and genomic instability

Original language description

Accurate replication of DNA requires stringent regulation to ensure genome integrity. In human cells, thousands of origins of replication are coordinately activated during S phase, and the velocity of replication forks is adjusted to fully replicate DNA in pace with the cell cycle(1). Replication stress induces fork stalling and fuels genome instability(2). The mechanistic basis of replication stress remains poorly understood despite its emerging role in promoting cancer(2). Here we show that inhibition of poly(ADP-ribose) polymerase (PARP) increases the speed of fork elongation and does not cause fork stalling, which is in contrast to the accepted model in which inhibitors of PARP induce fork stalling and collapse3. Aberrant acceleration of fork progression by 40% above the normal velocity leads to DNA damage. Depletion of the treslin or MTBP proteins, which are involved in origin firing, also increases fork speed above the tolerated threshold, and induces the DNA damage response pathway. Mechanistically, we show that poly(ADP-ribosyl) ation (PARylation) and the PCNA interactor p21(Cip1) (p21) are crucial modulators of fork progression. PARylation and p21 act as suppressors of fork speed in a coordinated regulatory network that is orchestrated by the PARP1 and p53 proteins. Moreover, at the fork level, PARylation acts as a sensor of replication stress. During PARP inhibition, DNA lesions that induce fork arrest and are normally resolved or repaired remain unrecognized by the replication machinery. Conceptually, our results show that accelerated replication fork progression represents a general mechanism that triggers replication stress and the DNA damage response. Our findings contribute to a better understanding of the mechanism of fork speed control, with implications for genomic (in) stability and rational cancer treatment.

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

10608 - Biochemistry and molecular biology

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

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

Name of the periodical

Nature

ISSN

0028-0836

e-ISSN

—

Volume of the periodical

559

Issue of the periodical within the volume

7713

Country of publishing house

GB - UNITED KINGDOM

Number of pages

6

Pages from-to

279-284

UT code for WoS article

000438240900061

EID of the result in the Scopus database

2-s2.0-85049788125