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

// Carmit Strauss 1 , Maya Kornowski 1 , Avraham Benvenisty 1 , Amit Shahar 2 , Hadas Masury 2 , Ittai Ben-Porath 2 , Tommer Ravid 3 , Ayelet Arbel-Eden 4 , Michal Goldberg 1 1 Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel 2 Department of Developmental Biology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel 3 Department of Biochemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel 4 Department of Medical Laboratory Sciences, Hadassah Academic College, Jerusalem, 91010, Israel Correspondence to: Michal Goldberg, e-mail: goldbergm@mail.huji.ac.il Keywords: Estrogen-dependent cancers, DNA helicases, DNA nucleases, DNA2, estrogen, DNA damage response Received: June 30, 2014      Accepted: August 28, 2014      Published: November 01, 2014 ABSTRACT 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 being impaired in DNA2 activity, potentially promoting genomic instability and triggering cancer development.