title: The DNA2 nuclease/helicase is an estrogen-dependent gene mutated in breast and ovarian cancers.
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 impaired in DNA2 activity, potentially promoting genomic instability and triggering cancer development.
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: Carmit
authors.initials: C
authors.lastname: Strauss
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: Maya
authors.initials: M
authors.lastname: Kornowski
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Benvenisty
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
authors.forename: Amit
authors.initials: A
authors.lastname: Shahar
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
authors.forename: Hadas
authors.initials: H
authors.lastname: Masury
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
authors.forename: Ittai
authors.initials: I
authors.lastname: Ben-Porath
authors.affiliation: Department of Biochemistry, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: Tommer
authors.initials: T
authors.lastname: Ravid
authors.affiliation: Department of Medical Laboratory Sciences, Hadassah Academic College, Jerusalem, 91010, Israel.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Arbel-Eden
authors.affiliation: Department of Genetics, Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, 91904, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Goldberg
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D009368:Neoplasm Transplantation; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000401:mortality; D034622:RNA Interference; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D004967:Estrogens; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D004265:DNA Helicases; C509908:DNA2 protein, human