Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development | Zendy

Assaf C. Bester | Zendy; Maayan Roniger | Zendy; Yifat S. Oren | Zendy; Michael M. Im | Zendy; Dan Sarni | Zendy; Malka Chaoat | Zendy; Aaron Bensimon | Zendy; Gideon Zamir | Zendy; Donna S. Shewach | Zendy; Batsheva Kerem | Zendy

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Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development

Author(s) -

Assaf C. Bester,

Maayan Roniger,

Yifat S. Oren,

Michael M. Im,

Dan Sarni,

Malka Chaoat,

Aaron Bensimon,

Gideon Zamir,

Donna S. Shewach,

Batsheva Kerem

Publication year - 2011

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2011.03.044

Subject(s) - biology , genome instability , dna replication , dna re replication , carcinogenesis , microbiology and biotechnology , genetics , cell cycle , transcription (linguistics) , dna damage , transcription factor , dna repair , gene , dna , cancer research , eukaryotic dna replication , linguistics , philosophy

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.

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