Nucleotide deficiency promotes genomic instability in early stages of cancer development

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

doi:10.1016/j.cell.2011.03.044

Nucleotide deficiency promotes genomic instability in early stages of cancer development

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

^*Corresponding author for this work

Department of Genetics

Research output: Contribution to journal › Article › peer-review

702 Scopus citations

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.

Original language	English
Pages (from-to)	435-446
Number of pages	12
Journal	Cell
Volume	145
Issue number	3
DOIs	https://doi.org/10.1016/j.cell.2011.03.044
State	Published - 29 Apr 2011

Bibliographical note

Funding Information:
The authors thank Prof. Levana Sherman for the LXSN vectors and for helpful advice, Dr. Tzipora Shlomai for the F1 cells, and Prof. Jiri Bartek for the pbabe-puro-cyclin E vector. This work was partially supported by a grant from the Nachmias Foundation of the Hebrew University, France-Israel program of the Israeli Ministry of Science, and the Israel Ministry of Health.

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10.1016/j.cell.2011.03.044

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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.",

author = "Bester, \{Assaf C.\} and Maayan Roniger and Oren, \{Yifat S.\} and Im, \{Michael M.\} and Dan Sarni and Malka Chaoat and Aaron Bensimon and Gideon Zamir and Shewach, \{Donna S.\} and Batsheva Kerem",

note = "Funding Information: The authors thank Prof. Levana Sherman for the LXSN vectors and for helpful advice, Dr. Tzipora Shlomai for the F1 cells, and Prof. Jiri Bartek for the pbabe-puro-cyclin E vector. This work was partially supported by a grant from the Nachmias Foundation of the Hebrew University, France-Israel program of the Israeli Ministry of Science, and the Israel Ministry of Health. ",

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doi = "10.1016/j.cell.2011.03.044",

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AU - Bester, Assaf C.

AU - Roniger, Maayan

AU - Oren, Yifat S.

AU - Im, Michael M.

AU - Sarni, Dan

AU - Chaoat, Malka

AU - Bensimon, Aaron

AU - Zamir, Gideon

AU - Shewach, Donna S.

AU - Kerem, Batsheva

N1 - Funding Information: The authors thank Prof. Levana Sherman for the LXSN vectors and for helpful advice, Dr. Tzipora Shlomai for the F1 cells, and Prof. Jiri Bartek for the pbabe-puro-cyclin E vector. This work was partially supported by a grant from the Nachmias Foundation of the Hebrew University, France-Israel program of the Israeli Ministry of Science, and the Israel Ministry of Health.

PY - 2011/4/29

Y1 - 2011/4/29

N2 - 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.

AB - 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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Nucleotide deficiency promotes genomic instability in early stages of cancer development

Abstract

Bibliographical note

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