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Mammalian DNA2 helicase/nuclease cleaves G-quadruplex DNA and is required for telomere integrity

Lin, Weiqiang and Sampathi, Shilpa and Dai, Huifang and Liu, Changwei and Zhou, Mian and Hu, Jenny and Huang, Qing and Campbell, Judith and Shin-Ya, Kazuo and Zheng, Li and Chai, Weihang and Shen, Binghui (2013) Mammalian DNA2 helicase/nuclease cleaves G-quadruplex DNA and is required for telomere integrity. EMBO Journal, 32 (10). pp. 1425-1439. ISSN 0261-4189. PMCID PMC3655473. https://resolver.caltech.edu/CaltechAUTHORS:20130719-153635651

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Abstract

Efficient and faithful replication of telomeric DNA is critical for maintaining genome integrity. The G-quadruplex (G4) structure arising in the repetitive TTAGGG sequence is thought to stall replication forks, impairing efficient telomere replication and leading to telomere instabilities. However, pathways modulating telomeric G4 are poorly understood, and it is unclear whether defects in these pathways contribute to genome instabilities in vivo. Here, we report that mammalian DNA2 helicase/nuclease recognizes and cleaves telomeric G4 in vitro. Consistent with DNA2’s role in removing G4, DNA2 deficiency in mouse cells leads to telomere replication defects, elevating the levels of fragile telomeres (FTs) and sister telomere associations (STAs). Such telomere defects are enhanced by stabilizers of G4. Moreover, DNA2 deficiency induces telomere DNA damage and chromosome segregation errors, resulting in tetraploidy and aneuploidy. Consequently, DNA2-deficient mice develop aneuploidy-associated cancers containing dysfunctional telomeres. Collectively, our genetic, cytological, and biochemical results suggest that mammalian DNA2 reduces replication stress at telomeres, thereby preserving genome stability and suppressing cancer development, and that this may involve, at least in part, nucleolytic processing of telomeric G4.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1038/emboj.2013.88DOIArticle
http://www.nature.com/emboj/journal/v32/n10/full/emboj201388a.htmlPublisherArticle
http://www.nature.com/emboj/journal/v32/n10/suppinfo/emboj201388as1.htmlPublisherSupplementary Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655473/PubMed CentralArticle
ORCID:
AuthorORCID
Zheng, Li0000-0002-3744-185X
Shen, Binghui0000-0002-4408-407X
Additional Information:© 2013 European Molecular Biology Organization. Received: 30 October 2012; accepted: 26 March 2013; published online: 19 April 2013. We thank T de Lange for providing polyclonal antibodies against TRF1 or TRF2 and vectors expressing Myc-tagged mouse TRF1 and TRF2. We thank V Bedell D in the City of Hope Cytogenetics Core Facility for technical assistance with quantitative FISH analysis of tissue sections. We thank M Lee and B Armstrong in the City of Hope Microscopy Core Facility for assistance with IF. SS was supported by Poncin Trust Fellowship. This work was supported by NIH grants R01CA085344 to BS, and R15GM099008 and R21AG041375 to WC. Author contributions: LZ, WC, BS conceived, designed, and supervised the study. WL, HD, JH, and LZ performed biochemical assays on recombinant DNA2 and characterized WT and DNA2 mutant mice. CL, MZ and JC performed recombinant DNA2 expression and purification. KS performed purification of telomestatin and contributed to the assay of FTs in the presence of the G4 stabilization molecules. SS, LZ, andWC performed experiments in vitro and in vivo to analyse telomeres in WT and DNA2 mutant cells. QH performed histological analyses. WL, SS, JC, LZ, WC, and BS analysed and interpreted data. LZ, WC, JC, and BS wrote the manuscript.
Funders:
Funding AgencyGrant Number
Poncin Trust FellowshipUNSPECIFIED
NIHR01CA085344
NIHR15GM099008
NIHR21AG041375
Subject Keywords:aneuploidy; cancer; DNA2 nuclease; G4; telomere
Issue or Number:10
PubMed Central ID:PMC3655473
Record Number:CaltechAUTHORS:20130719-153635651
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20130719-153635651
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:39475
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:22 Jul 2013 21:22
Last Modified:09 Mar 2020 13:19

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