Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development

By A. Bester, M. Roniger, Y. Oren, M. Im, Dan Sarni, Malka Chaoat, A. Bensimon, G. Zamir, D. Shewach, B. Kerem. Cell, 2011

849 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/8d931c4a7e1d1eb76859aeac9f957e001f3ce179

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In Molecular Biology

1. Morgane Macheret
2. Matthew A. Spence
3. Paul Robson
4. Bing Lim
5. Da Xu
6. N. Ando
7. Colin Jackson
8. Anja Groth

In Oncology

1. Morgane Macheret
2. T. Halazonetis
3. Philipp Kaldis
4. Y. Fouad
5. C. Aanei

Citations in the corpus

• Analysis of insertions and extensions in the functional evolution of the ribonucleotide reductase family (2022, background): “This so-called specificity site is allosterically coupled to the active site via another functional insertion called loop 2 (Figure 1a and Figure S1b, red),(7) such that the proper balance of nucleotides for DNA synthesis is maintained.(8,9) Remarkably, in monomeric class II RNRs, the loop 1 inserti”
• Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. (2012, positive): “involves aberrant activation of cell proliferation, which then leads to a crisis of nucleotide deficiency and replication stress (Bester et al., 2011)—a crisis that GLDC upregulation could overcome for continued progression in tumorigenesis.”
• Chromatin replication and epigenome maintenance (2012, background): “Given that oncogenic activity can trigger replication stres”
• DNA replication stress as a hallmark of cancer. (2015, background): “Taking into account that the ATM/TP53/MDM2 pathway responds to DNA DSBs, we and others proposed that DSBs are present in precancerous and cancerous cells (55–59).”