TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity
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.
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.Attached Files
Published - gkz537.pdf
Supplemental Material - gkz537_supplemental_file.pdf
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Additional details
- PMCID
- PMC6698806
- Eprint ID
- 96657
- Resolver ID
- CaltechAUTHORS:20190624-094128477
- R01CA085344
- NIH
- R50CA211397
- NIH
- National Cancer Institute
- Created
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2019-06-24Created from EPrint's datestamp field
- Updated
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2022-02-25Created from EPrint's last_modified field