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Nucleotide deficiency promotes genomic instability in early stages of cancer development.
Cell. 2011 Apr 29; 145(3):435-46
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31 May 2011
New Finding
DOI: 10.3410/f.10858958.11778057
This paper is of particular interest as it reveals that changes in cellular deoxyribonucleotide triphosphate (dNTP) pools induced by oncogenes are directly involved in cancer development.
It is now well established that oncogene-induced cell proliferation promotes genomic instability by causing DNA replication...Continue reading
It is now well established that oncogene-induced cell proliferation promotes genomic instability by causing DNA replication...Continue reading
This paper is of particular interest as it reveals that changes in cellular deoxyribonucleotide triphosphate (dNTP) pools induced by oncogenes are directly involved in cancer development.
It is now well established that oncogene-induced cell proliferation promotes genomic instability by causing DNA replication stress {1,2}. However, the nature of the link between oncogene activation and replication defects is not known. In this article, Batsheva Kerem and colleagues report the surprising observation that aberrant activation of the Rb-E2F pathway in primary human keratinocytes by the human papillomavirus (HPV) E6/E7 oncoproteins reduces intracellular dNTP pools. In normal growth conditions, nucleotide levels are tightly controlled by multiple mechanisms and are coupled to DNA replication {3}. In E6/E7-expressing cells, the authors propose that dNTP synthesis is uncoupled from cell proliferation, leading to dNTP shortage and accumulation of replication-dependent DNA damage. Remarkably, addition of exogenous nucleosides in the culture media reduced both replication defects and colony outgrowth in soft agar, supporting the view that low dNTP pools contribute to cellular transformation. Together, these results shed new light on the origin of replication stress in oncogene-induced cells. Further work will be required to understand how dNTP levels are regulated during cell proliferation and how DNA replication under low-dNTP conditions induces genomic instability.
It is now well established that oncogene-induced cell proliferation promotes genomic instability by causing DNA replication stress {1,2}. However, the nature of the link between oncogene activation and replication defects is not known. In this article, Batsheva Kerem and colleagues report the surprising observation that aberrant activation of the Rb-E2F pathway in primary human keratinocytes by the human papillomavirus (HPV) E6/E7 oncoproteins reduces intracellular dNTP pools. In normal growth conditions, nucleotide levels are tightly controlled by multiple mechanisms and are coupled to DNA replication {3}. In E6/E7-expressing cells, the authors propose that dNTP synthesis is uncoupled from cell proliferation, leading to dNTP shortage and accumulation of replication-dependent DNA damage. Remarkably, addition of exogenous nucleosides in the culture media reduced both replication defects and colony outgrowth in soft agar, supporting the view that low dNTP pools contribute to cellular transformation. Together, these results shed new light on the origin of replication stress in oncogene-induced cells. Further work will be required to understand how dNTP levels are regulated during cell proliferation and how DNA replication under low-dNTP conditions induces genomic instability.
References
1.
Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.
Nature 2006 Nov 30; 7119(444):633-7
PMID: 17136093
2.
Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication.
Nature 2006 Nov 30; 7119(444):638-42
PMID: 17136094
3.
DNA building blocks at the foundation of better survival.
Cell Cycle 2003 May-Jun; 3(2):171-3
PMID: 12734415
Disclosures
None declared
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Pasero P: F1000Prime Recommendation of [Bester AC et al., Cell 2011, 145(3):435-46]. In F1000Prime, 31 May 2011; DOI: 10.3410/f.10858958.11778057. F1000Prime.com/10858958#eval11778057
F1000Prime Recommendations, Dissents and Comments for [Bester AC et al., Cell 2011, 145(3):435-46]. In F1000Prime, 23 May 2013; F1000Prime.com/10858958
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Chromosomal instability in early cancer stages is caused by stress on DNA replication. The molecular basis for replication perturbation in this context is currently unknown. We studied the replication dynamics in cells in which a regulator of S phase entry and cell proliferation, the Rb-E2F pathway, is aberrantly activated. Aberrant activation of this pathway by HPV-16 E6/E7 or cyclin E oncogenes significantly decreased the cellular nucleotide levels in the newly transformed cells. Exogenously supplied nucleosides rescued the replication stress and DNA damage and dramatically decreased oncogene-induced transformation. Increased transcription of nucleotide biosynthesis genes, mediated by expressing the transcription factor c-myc, increased the nucleotide pool and also rescued the replication-induced DNA damage. Our results suggest a model for early oncogenesis in which uncoordinated activation of factors regulating cell proliferation leads to insufficient nucleotides that fail to support normal replication and genome stability.
DOI: 10.1016/j.cell.2011.03.044
PMID: 21529715
