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.
Highlights
Chromosomal instability is a hallmark of most solid tumors and adult-onset leukemias (Hanahan & Weinberg, 2011)
To investigate the role of folate levels in tumorigenesis, we first analyzed the effects of folate deficiency on DNA replication dynamics
We show that the extent of replication stress plays an important role in prompting genomic instability and tumor development in vivo (Figs 3–5)
Summary
Chromosomal instability is a hallmark of most solid tumors and adult-onset leukemias (Hanahan & Weinberg, 2011). Several mechanisms by which oncogenes induce replication stress were recently identified, including insufficient nucleotide pools to support the extensive enforced DNA replication (Bester et al, 2011; Mannava et al, 2013), interference with the pre-replication complex assembly (Ekholm-Reed et al, 2004) and the collision between replication and transcription (Jones et al, 2013). It remains unclear whether the extent of the replication stress can affect the probability of neoplastic transformation. Whether enhanced replication stress can be driven by a combination of genetic, cellular, and environmental factors is largely unknown
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