ArticleCell cycle (Georgetown, Tex.)2014
Preventing over-resection by DNA2 helicase/nuclease suppresses repair defects in Fanconi anemia cells.
Article in Cell cycle (Georgetown, Tex.), 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 67 citations in OpenAlex.
- Multi-omics analysis positions DNA2 at the interface of genome integrity programs and tumor behavior in pan-cancer.Functional & integrative genomics · 2026Article
- ATM promotes reversed fork processing during DNA interstrand cross-link repair.bioRxiv : the preprint server for biology · 2025Article
- Article
- Cytosolic DNA and intracellular CaDNA repair · 2025Review
- Proteasome-mediated degradation of long-range nucleases negatively regulates resection of DNA double-strand breaks.iScience · 2024Article
- TCAF1 promotes TRPV2-mediated CaNature communications · 2024Article
- FANCD2 and RAD51 recombinase directly inhibit DNA2 nuclease at stalled replication forks and FANCD2 acts as a novel RAD51 mediator in strand exchange to promote genome stability.Nucleic acids research · 2023Article
- Actin nucleators safeguard replication forks by limiting nascent strand degradation.Nucleic acids research · 2023Article
- Cdc14 phosphatase counteracts Cdk-dependent Dna2 phosphorylation to inhibit resection during recombinational DNA repair.Nature communications · 2023Article
- Actin nucleators safeguard replication forks by limiting nascent strand degradation.bioRxiv : the preprint server for biology · 2023Article
- The emerging determinants of replication fork stability.Nucleic acids research · 2021Review
- Review
- A Surge of DNA Damage Links Transcriptional Reprogramming and Hematopoietic Deficit in Fanconi Anemia.Molecular cell · 2020Article
- FANCJ compensates for RAP80 deficiency and suppresses genomic instability induced by interstrand cross-links.Nucleic acids research · 2020Article
- Fanconi anemia and the underlying causes of genomic instability.Environmental and molecular mutagenesis · 2020Review
- Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links.Genes & development · 2020Article
- Multiple roles of DNA2 nuclease/helicase in DNA metabolism, genome stability and human diseases.Nucleic acids research · 2020Review
- TRAF6 mediates human DNA2 polyubiquitination and nuclear localization to maintain nuclear genome integrity.Nucleic acids research · 2019Article
- EXD2 Protects Stressed Replication Forks and Is Required for Cell Viability in the Absence of BRCA1/2.Molecular cell · 2019Article
- CaMolecular cell · 2019Article
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Authors and funding
4 authors at 2 institutions in 2 countries.
Funding
Abstract
FANCD2 is required for the repair of DNA damage by the FA (Fanconi anemia) pathway, and, consequently, FANCD2-deficient cells are sensitive to compounds such as cisplatin and formaldehyde that induce DNA:DNA and DNA:protein crosslinks, respectively. The DNA2 helicase/nuclease is required for RNA/DNA flap removal from Okazaki fragments during DNA replication and for the resection of DSBs (double-strand breaks) during HDR (homology-directed repair) of replication stress-induced damage. A knockdown of DNA2 renders normal cells as sensitive to cisplatin (in the absence of EXO1) and to formaldehyde (even in the presence of EXO1) as FANCD2(-/-) cells. Surprisingly, however, the depletion of DNA2 in FANCD2-deficient cells rescues the sensitivity of FANCD2(-/-) cells to cisplatin and formaldehyde. We previously showed that the resection activity of DNA2 acts downstream of FANCD2 to insure HDR of the DSBs arising when replication forks encounter ICL (interstrand crosslink) damage. The suppression of FANCD2(-/-) by DNA2 knockdowns suggests that DNA2 and FANCD2 also have antagonistic roles: in the absence of FANCD2, DNA2 somehow corrupts repair. To demonstrate that DNA2 is deleterious to crosslink repair, we used psoralen-induced ICL damage to trigger the repair of a site-specific crosslink in a GFP reporter and observed that "over-resection" can account for reduced repair. Our work demonstrates that excessive resection can lead to genome instability and shows that strict regulatory processes have evolved to inhibit resection nucleases. The suppression of FANCD2(-/-) phenotypes by DNA2 depletion may have implications for FA therapies and for the use of ICL-inducing agents in chemotherapy.
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