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Published January 10, 2020 | Published
Journal Article Open

Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases


DNA2 nuclease/helicase is a structure-specific nuclease, 5′-to-3′ helicase, and DNA-dependent ATPase. It is involved in multiple DNA metabolic pathways, including Okazaki fragment maturation, replication of 'difficult-to-replicate' DNA regions, end resection, stalled replication fork processing, and mitochondrial genome maintenance. The participation of DNA2 in these different pathways is regulated by its interactions with distinct groups of DNA replication and repair proteins and by post-translational modifications. These regulatory mechanisms induce its recruitment to specific DNA replication or repair complexes, such as DNA replication and end resection machinery, and stimulate its efficient cleavage of various structures, for example, to remove RNA primers or to produce 3′ overhangs at telomeres or double-strand breaks. Through these versatile activities at replication forks and DNA damage sites, DNA2 functions as both a tumor suppressor and promoter. In normal cells, it suppresses tumorigenesis by maintaining the genomic integrity. Thus, DNA2 mutations or functional deficiency may lead to cancer initiation. However, DNA2 may also function as a tumor promoter, supporting cancer cell survival by counteracting replication stress. Therefore, it may serve as an ideal target to sensitize advanced DNA2-overexpressing cancers to current chemo- and radiotherapy regimens.

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 June 25, 2019; Revised October 23, 2019; Editorial Decision November 04, 2019; Accepted November 12, 2019; Published: 22 November 2019. The authors are grateful for productive collaborations with R.A. Bambara (Rochester University), W. Chai (Washington State University), S. Stewart (Washington University School of Medicine), D.F. Bogenhagen (Stony Brook University School of Medicine), G.P. Comi (University of Milan), and Tanya Paull (UT Austin) which resulted in several lines of evidence on novel structure and functions of DNA2 discussed in this review. We also thank Kerin Higa for editorial assistance. The authors regret that this article could not cite all the pertinent articles due to space limitations. Funding: National Institutes of Health/National Cancer Institute [R01CA085344 to B.H.S., R01GM123554 to J.L.C., R50CA211397 to L.Z.]. Funding for open access charge: National Institutes of Health [R01CA085344 to B.H.S.] Conflict of interest statement: None declared.

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