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Stabilization of G-quadruplex DNA structures in Schizosaccharomyces pombe causes single-strand DNA lesions and impedes DNA replication
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0003-0364-8964
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.ORCID iD: 0000-0001-6871-7663
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2020 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 48, no 19, p. 10998-11015Article in journal (Refereed) Published
Abstract [en]

G-quadruplex (G4) structures are stable noncanonical DNA structures that are implicated in the regulation of many cellular pathways. We show here that the G4-stabilizing compound PhenDC3 causes growth defects in Schizosaccharomyces pombe cells, especially during S-phase in synchronized cultures. By visualizing individual DNA molecules, we observed shorter DNA fragments of newly replicated DNA in the PhenDC3-treated cells, suggesting that PhenDC3 impedes replication fork progression. Furthermore, a novel single DNA molecule damage assay revealed increased single-strand DNA lesions in the PhenDC3-treated cells. Moreover, chromatin immunoprecipitation showed enrichment of the leading-strand DNA polymerase at sites of predicted G4 structures, suggesting that these structures impede DNA replication. We tested a subset of these sites and showed that they form G4 structures, that they stall DNA synthesis in vitro and that they can be resolved by the breast cancerassociated Pif1 family helicases. Our results thus suggest that G4 structures occur in S. pombe and that stabilized/unresolved G4 structures are obstacles for the replication machinery. The increased levels of DNA damage might further highlight the association of the human Pif1 helicase with familial breast cancer and the onset of other human diseases connected to unresolved G4 structures.

Place, publisher, year, edition, pages
Oxford University Press, 2020. Vol. 48, no 19, p. 10998-11015
National Category
Medical and Health Sciences
Research subject
molecular medicine (genetics and pathology); Medical Biochemistry
Identifiers
URN: urn:nbn:se:umu:diva-176331DOI: 10.1093/nar/gkaa820ISI: 000606018400033Scopus ID: 2-s2.0-85095799661OAI: oai:DiVA.org:umu-176331DiVA, id: diva2:1484633
Funder
Knut and Alice Wallenberg Foundation, KAW2015–0189Swedish Research Council, 2018–02651Swedish Research Council, 2017–05235Swedish Cancer Society, 2019/126Swedish Cancer Society, 2017/654The Kempe Foundations, SMK-1632Swedish Childhood Cancer Foundation, MT2016–0004Swedish Childhood Cancer Foundation, PR2019–0037Swedish Research Council, 2018–02651Available from: 2020-10-29 Created: 2020-10-29 Last updated: 2023-03-24Bibliographically approved

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Obi, IkennaRentoft, MatildaJamroskovic, JanChand, KaramChorell, ErikSabouri, Nasim

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