title: Folate levels modulate oncogene-induced replication stress and tumorigenicity.
abstract: Chromosomal instability in early cancer stages is caused by replication stress. One mechanism by which oncogene expression induces replication stress is to drive cell proliferation with insufficient nucleotide levels. Cancer development is driven by alterations in both genetic and environmental factors. Here, we investigated whether replication stress can be modulated by both genetic and non-genetic factors and whether the extent of replication stress affects the probability of neoplastic transformation. To do so, we studied the effect of folate, a micronutrient that is essential for nucleotide biosynthesis, on oncogene-induced tumorigenicity. We show that folate deficiency by itself leads to replication stress in a concentration-dependent manner. Folate deficiency significantly enhances oncogene-induced replication stress, leading to increased DNA damage and tumorigenicity in vitro. Importantly, oncogene-expressing cells, when grown under folate deficiency, exhibit a significantly increased frequency of tumor development in mice. These findings suggest that replication stress is a quantitative trait affected by both genetic and non-genetic factors and that the extent of replication stress plays an important role in cancer development.
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences Edmond J. Safra Campus The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Noa
authors.initials: N
authors.lastname: Lamm
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences Edmond J. Safra Campus The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Karin
authors.initials: K
authors.lastname: Maoz
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences Edmond J. Safra Campus The Hebrew University of Jerusalem, Jerusalem, Israel.
authors.forename: Assaf C
authors.initials: AC
authors.lastname: Bester
authors.affiliation: Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Im
authors.affiliation: Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, MI, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Shewach
authors.affiliation: Department of Biochemistry and Molecular Biology, Institute for Medical Research Israel-Canada The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
authors.forename: Rotem
authors.initials: R
authors.lastname: Karni
authors.affiliation: Department of Genetics, The Alexander Silberman Institute of Life Sciences Edmond J. Safra Campus The Hebrew University of Jerusalem, Jerusalem, Israel kerem@cc.huji.ac.il.
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000187:drug effects*; D004261:DNA Replication / Q000187:drug effects*; D005492:Folic Acid / Q000378:metabolism*; D042822:Genomic Instability / Q000187:drug effects*; D051379:Mice; D009857:Oncogenes / Q000187:drug effects*
chemical_list: D005492:Folic Acid
keywords: cancer development; chromosomal instability; folate deficiency; oncogene expression; replication stress