Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling

Lee, Wei Ting C.; Yin, Yandong; Morten, Michael J.; Tonzi, Peter; Gwo, Pam Pam; Odermatt, Diana C.; Modesti, Mauro; Cantor, Sharon B.; Gari, Kerstin; Huang, Tony T.; Rothenberg, Eli

doi:10.1038/s41467-021-22830-9

Please use this identifier to cite or link to this item: https://doi.org/10.21256/zhaw-25785

Publication type:	Article in scientific journal
Type of review:	Peer review (publication)
Title:	Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling
Authors:	Lee, Wei Ting C. Yin, Yandong Morten, Michael J. Tonzi, Peter Gwo, Pam Pam Odermatt, Diana C. Modesti, Mauro Cantor, Sharon B. Gari, Kerstin Huang, Tony T. Rothenberg, Eli
et. al:	No
DOI:	10.1038/s41467-021-22830-9 10.21256/zhaw-25785
Published in:	Nature Communications
Volume(Issue):	12
Issue:	1
Page(s):	2525
Issue Date:	2021
Publisher / Ed. Institution:	Nature Publishing Group
ISSN:	2041-1723
Language:	English
Subject (DDC):	572: Biochemistry
Abstract:	Guanine-rich DNA sequences occur throughout the human genome and can transiently form G-quadruplex (G4) structures that may obstruct DNA replication, leading to genomic instability. Here, we apply multi-color single-molecule localization microscopy (SMLM) coupled with robust data-mining algorithms to quantitatively visualize replication fork (RF)-coupled formation and spatial-association of endogenous G4s. Using this data, we investigate the effects of G4s on replisome dynamics and organization. We show that a small fraction of active replication forks spontaneously form G4s at newly unwound DNA immediately behind the MCM helicase and before nascent DNA synthesis. These G4s locally perturb replisome dynamics and organization by reducing DNA synthesis and limiting the binding of the single-strand DNA-binding protein RPA. We find that the resolution of RF-coupled G4s is mediated by an interplay between RPA and the FANCJ helicase. FANCJ deficiency leads to G4 accumulation, DNA damage at G4-associated replication forks, and silencing of the RPA-mediated replication stress response. Our study provides first-hand evidence of the intrinsic, RF-coupled formation of G4 structures, offering unique mechanistic insights into the interference and regulation of stable G4s at replication forks and their effect on RPA-associated fork signaling and genomic instability.
URI:	https://digitalcollection.zhaw.ch/handle/11475/25785
Fulltext version:	Published version
License (according to publishing contract):	CC BY 4.0: Attribution 4.0 International
Departement:	Life Sciences and Facility Management
Organisational Unit:	Institute of Chemistry and Biotechnology (ICBT)
Published as part of the ZHAW project:	Ein DNA-Reparaturprotein als Target in der Krebstherapie
Appears in collections:	Publikationen Life Sciences und Facility Management

Files in This Item:

File	Description	Size	Format
2021_Lee-etal_Single-molecule-imaging-reveals-replication-fork_nc.pdf		8.89 MB	Adobe PDF	View/Open

Show full item record

Lee, W. T. C., Yin, Y., Morten, M. J., Tonzi, P., Gwo, P. P., Odermatt, D. C., Modesti, M., Cantor, S. B., Gari, K., Huang, T. T., & Rothenberg, E. (2021). Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling. Nature Communications, 12(1), 2525. https://doi.org/10.1038/s41467-021-22830-9

Lee, W.T.C. et al. (2021) ‘Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling’, Nature Communications, 12(1), p. 2525. Available at: https://doi.org/10.1038/s41467-021-22830-9.

W. T. C. Lee et al., “Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling,” Nature Communications, vol. 12, no. 1, p. 2525, 2021, doi: 10.1038/s41467-021-22830-9.

LEE, Wei Ting C., Yandong YIN, Michael J. MORTEN, Peter TONZI, Pam Pam GWO, Diana C. ODERMATT, Mauro MODESTI, Sharon B. CANTOR, Kerstin GARI, Tony T. HUANG und Eli ROTHENBERG, 2021. Single-molecule imaging reveals replication fork coupled formation of G-quadruplex structures hinders local replication stress signaling. Nature Communications. 2021. Bd. 12, Nr. 1, S. 2525. DOI 10.1038/s41467-021-22830-9

Lee, Wei Ting C., Yandong Yin, Michael J. Morten, Peter Tonzi, Pam Pam Gwo, Diana C. Odermatt, Mauro Modesti, et al. 2021. “Single-Molecule Imaging Reveals Replication Fork Coupled Formation of G-Quadruplex Structures Hinders Local Replication Stress Signaling.” Nature Communications 12 (1): 2525. https://doi.org/10.1038/s41467-021-22830-9.

Lee, Wei Ting C., et al. “Single-Molecule Imaging Reveals Replication Fork Coupled Formation of G-Quadruplex Structures Hinders Local Replication Stress Signaling.” Nature Communications, vol. 12, no. 1, 2021, p. 2525, https://doi.org/10.1038/s41467-021-22830-9.