The DNA2 nuclease/helicase is an estrogen-dependent gene mutated in breast and ovarian cancers

Carmit Strauss, Maya Kornowski, Avraham Benvenisty, Amit Shahar, Hadas Masury, Ittai Ben-Porath, Tommer Ravid, Ayelet Arbel-Eden, Michal Goldberg*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


Genomic instability, a hallmark of cancer, is commonly caused by failures in the DNA damage response. Here we conducted a bioinformatical screen to reveal DNA damage response genes that are upregulated by estrogen and highly mutated in breast and ovarian cancers. This screen identified 53 estrogen-dependent cancer genes, some of which are novel. Notably, the screen retrieved 9 DNA helicases as well as 5 nucleases. DNA2, which functions as both a helicase and a nuclease and plays a role in DNA repair and replication, was retrieved in the screen. Mutations in DNA2, found in estrogen-dependent cancers, are clustered in the helicase and nuclease domains, suggesting activity impairment. Indeed, we show that mutations found in ovarian cancers impair DNA2 activity. Depletion of DNA2 in cells reduces their tumorogenicity in mice. In human, high expression of DNA2 correlates with poor survival of estrogen receptor-positive patients but not of estrogen receptor-negative patients. We also demonstrate that depletion of DNA2 in cells reduces proliferation, while addition of estrogen restores proliferation. These findings suggest that cells responding to estrogen will proliferate despite impaired in DNA2 activity, potentially promoting genomic instability and triggering cancer development.

Original languageAmerican English
Pages (from-to)9396-9409
Number of pages14
Issue number19
StatePublished - 2014


  • DNA damage response
  • DNA helicases
  • DNA nucleases
  • DNA2
  • Estrogen
  • Estrogen-dependent cancers


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