Folate levels modulate oncogene‐induced replication stress and tumorigenicity. Issue 9 (21st July 2015) - Lamm, Noa
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. Synopsis: Oncogene‐induced replication stress is shown here as a quantitative trait enhanced by non‐genetic factors such as the essential dietary nutrient folate. The combination of oncogene expression and folate deficiency enhances replication‐induced genomic instability and cancer development in vivo . Folate deficiency by itself leads to replication stress in a concentration‐dependent manner that can be rescued by nucleoside supplementation. The extent of oncogene‐induced replication stress can be enhanced by an additional source of stress, resulting in enhanced DNA damage. Activation of the DNA damage response pathways by ATM and ATR is enhanced by the combination of oncogene expression and folate deficiency. Tumorigenicity potential in vitro and tumor development in vivo caused by oncogene expression are significantly enhanced by folate deficiency. Abstract : Oncogene‐induced replication stress is shown here as a quantitative trait enhanced by non‐genetic factors such as the essential dietary nutrient folate. The combination of oncogene expression and folate deficiency enhances replication‐induced genomic instability and cancer development in vivo .