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The iron-sulphur cluster in human DNA2 is required for all biochemical activities of DNA2.
Commun Biol. 2020 Jun 23; 3(1):322.CB

Abstract

The nuclease/helicase DNA2 plays important roles in DNA replication, repair and processing of stalled replication forks. DNA2 contains an iron-sulphur (FeS) cluster, conserved in eukaryotes and in a related bacterial nuclease. FeS clusters in DNA maintenance proteins are required for structural integrity and/or act as redox-sensors. Here, we demonstrate that loss of the FeS cluster affects binding of human DNA2 to specific DNA substrates, likely through a conformational change that distorts the central DNA binding tunnel. Moreover, we show that the FeS cluster is required for DNA2's nuclease, helicase and ATPase activities. Our data also establish that oxidation of DNA2 impairs DNA binding in vitro, an effect that is reversible upon reduction. Unexpectedly, though, this redox-regulation is independent of the presence of the FeS cluster. Together, our study establishes an important structural role for the FeS cluster in human DNA2 and discovers a redox-regulatory mechanism to control DNA binding.

Authors+Show Affiliations

Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland. mariotti@imcr.uzh.ch.Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland.Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland.Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland.Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, 6500, Bellinzona, Switzerland. Department of Biology, Institute of Biochemistry, ETH Zurich, 8092, Zurich, Switzerland.Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland.Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland.Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, 6500, Bellinzona, Switzerland. Department of Biology, Institute of Biochemistry, ETH Zurich, 8092, Zurich, Switzerland.Institute of Molecular Cancer Research, University of Zurich, 8057, Zurich, Switzerland. gari@imcr.uzh.ch.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32576938

Citation

Mariotti, Laura, et al. "The Iron-sulphur Cluster in Human DNA2 Is Required for All Biochemical Activities of DNA2." Communications Biology, vol. 3, no. 1, 2020, p. 322.
Mariotti L, Wild S, Brunoldi G, et al. The iron-sulphur cluster in human DNA2 is required for all biochemical activities of DNA2. Commun Biol. 2020;3(1):322.
Mariotti, L., Wild, S., Brunoldi, G., Piceni, A., Ceppi, I., Kummer, S., Lutz, R. E., Cejka, P., & Gari, K. (2020). The iron-sulphur cluster in human DNA2 is required for all biochemical activities of DNA2. Communications Biology, 3(1), 322. https://doi.org/10.1038/s42003-020-1048-4
Mariotti L, et al. The Iron-sulphur Cluster in Human DNA2 Is Required for All Biochemical Activities of DNA2. Commun Biol. 2020 Jun 23;3(1):322. PubMed PMID: 32576938.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The iron-sulphur cluster in human DNA2 is required for all biochemical activities of DNA2. AU - Mariotti,Laura, AU - Wild,Sebastian, AU - Brunoldi,Giulia, AU - Piceni,Alessandra, AU - Ceppi,Ilaria, AU - Kummer,Sandra, AU - Lutz,Richard E, AU - Cejka,Petr, AU - Gari,Kerstin, Y1 - 2020/06/23/ PY - 2019/10/03/received PY - 2020/06/03/accepted PY - 2020/6/25/entrez PY - 2020/6/25/pubmed PY - 2020/6/25/medline SP - 322 EP - 322 JF - Communications biology JO - Commun Biol VL - 3 IS - 1 N2 - The nuclease/helicase DNA2 plays important roles in DNA replication, repair and processing of stalled replication forks. DNA2 contains an iron-sulphur (FeS) cluster, conserved in eukaryotes and in a related bacterial nuclease. FeS clusters in DNA maintenance proteins are required for structural integrity and/or act as redox-sensors. Here, we demonstrate that loss of the FeS cluster affects binding of human DNA2 to specific DNA substrates, likely through a conformational change that distorts the central DNA binding tunnel. Moreover, we show that the FeS cluster is required for DNA2's nuclease, helicase and ATPase activities. Our data also establish that oxidation of DNA2 impairs DNA binding in vitro, an effect that is reversible upon reduction. Unexpectedly, though, this redox-regulation is independent of the presence of the FeS cluster. Together, our study establishes an important structural role for the FeS cluster in human DNA2 and discovers a redox-regulatory mechanism to control DNA binding. SN - 2399-3642 UR - https://www.unboundmedicine.com/medline/citation/32576938/The_iron-sulphur_cluster_in_human_DNA2_is_required_for_all_biochemical_activities_of_DNA2 L2 - https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32576938/ DB - PRIME DP - Unbound Medicine ER -
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