title: Nucleotide deficiency promotes genomic instability in early stages of cancer development.
abstract: 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.
authors.affiliation: Department of Genetics, The Life Sciences Institute, Edmond J. Safra Campus, The Hebrew University, Jerusalem, Israel.
authors.forename: Assaf C
authors.initials: AC
authors.lastname: Bester
authors.forename: Maayan
authors.initials: M
authors.lastname: Roniger
authors.forename: Yifat S
authors.initials: YS
authors.lastname: Oren
authors.forename: Michael M
authors.initials: MM
authors.lastname: Im
authors.forename: Dan
authors.initials: D
authors.lastname: Sarni
authors.forename: Malka
authors.initials: M
authors.lastname: Chaoat
authors.forename: Aaron
authors.initials: A
authors.lastname: Bensimon
authors.forename: Gideon
authors.initials: G
authors.lastname: Zamir
authors.forename: Donna S
authors.initials: DS
authors.lastname: Shewach
authors.forename: Batsheva
authors.initials: B
authors.lastname: Kerem
mesh_terms: D019927:Cyclin E / Q000378:metabolism; D004261:DNA Replication; D050684:E2F Transcription Factors / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D019656:Loss of Heterozygosity; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009711:Nucleotides / Q000096:biosynthesis* / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D050725:Papillomavirus E7 Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D016196:S Phase
chemical_list: D019927:Cyclin E; D050684:E2F Transcription Factors; C068651:E6 protein, Human papillomavirus type 16; D009711:Nucleotides; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D012097:Repressor Proteins; D016160:Retinoblastoma Protein; C059731:oncogene protein E7, Human papillomavirus type 16