Folate levels modulate oncogene-induced replication stress and tumorigenicity

Noa Lamm, Karin Maoz, Assaf C. Bester, Michael M. Im, Donna S. Shewach, Rotem Karni, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

26 Scopus citations


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.

Original languageAmerican English
Pages (from-to)1138-1152
Number of pages15
JournalEMBO Molecular Medicine
Issue number9
StatePublished - 1 Sep 2015

Bibliographical note

Publisher Copyright:
© 2015 The Authors.


  • Cancer development
  • Chromosomal instability
  • Folate deficiency
  • Oncogene expression
  • Replication stress


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