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TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity

Meng, Yuan and Liu, Changwei and Shen, Lei and Zhou, Mian and Liu, Wenpeng and Kowolik, Claudia and Campbell, Judith L. and Zheng, Li and Shen, Binghui (2019) TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity. Nucleic Acids Research, 47 (14). pp. 7564-7579. ISSN 0305-1048. PMCID PMC6698806. https://resolver.caltech.edu/CaltechAUTHORS:20190624-094128477

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Abstract

The multifunctional human DNA2 (hDNA2) nuclease/helicase is required to process DNA ends for homology-directed recombination repair (HDR) and to counteract replication stress. To participate in these processes, hDNA2 must localize to the nucleus and be recruited to the replication or repair sites. However, because hDNA2 lacks the nuclear localization signal that is found in its yeast homolog, it is unclear how its migration into the nucleus is regulated during replication or in response to DNA damage. Here, we report that the E3 ligase TRAF6 binds to and mediates the K63-linked polyubiquitination of hDNA2, increasing the stability of hDNA2 and promoting its nuclear localization. Inhibiting TRAF6-mediated polyubiquitination abolishes the nuclear localization of hDNA2, consequently impairing DNA end resection and HDR. Thus, the current study reveals a mechanism for the regulation of hDNA2 localization and establishes that TRAF6-mediated hDNA2 ubiquitination activates DNA repair pathways to maintain nuclear genome integrity.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1093/nar/gkz537DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698806PubMed CentralArticle
ORCID:
AuthorORCID
Zheng, Li0000-0002-3744-185X
Shen, Binghui0000-0002-4408-407X
Additional Information:© 2019 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Received: 11 January 2019; Revision Received: 29 May 2019; Accepted: 07 June 2019; Published: 19 June 2019. The authors wish it to be known that, in their opinion, the first three authors should be regarded as Joint First Authors. We would like to thank the staff of the City of Hope Light Microscopy/Digital Imaging Core. We thank Kerin Higa for editorial assistance. Funding: National Cancer Institute [R01CA085344 to B.H.S., R50CA211397 to L.Z.]. Funding for open access charge: National Cancer Institute [R01CA085344]. Conflict of interest statement. None declared.
Funders:
Funding AgencyGrant Number
NIHR01CA085344
NIHR50CA211397
National Cancer InstituteUNSPECIFIED
Issue or Number:14
PubMed Central ID:PMC6698806
Record Number:CaltechAUTHORS:20190624-094128477
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190624-094128477
Official Citation:Yuan Meng, Changwei Liu, Lei Shen, Mian Zhou, Wenpeng Liu, Claudia Kowolik, Judith L Campbell, Li Zheng, Binghui Shen, TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity, Nucleic Acids Research, Volume 47, Issue 14, 22 August 2019, Pages 7564–7579, https://doi.org/10.1093/nar/gkz537
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:96657
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:24 Jun 2019 17:03
Last Modified:09 Mar 2020 13:19

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