Nucleotide Deficiency Promotes Genomic Instability in Early Stages of Cancer Development

被引：666

作者：

Bester, Assaf C. ^{[1
]}

Roniger, Maayan ^{[1
]}

Oren, Yifat S. ^{[1
]}

Im, Michael M. ^{[3
]}

Sarni, Dan ^{[1
]}

Chaoat, Malka ^{[2
]}

Bensimon, Aaron ^{[4
]}

Zamir, Gideon ^{[2
]}

Shewach, Donna S. ^{[3
]}

Kerem, Batsheva ^{[1
]}

机构：

[1] Hebrew Univ Jerusalem, Dept Genet, Inst Life Sci, IL-91905 Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Dept Surg, Hadassah Med Sch, IL-91905 Jerusalem, Israel

[3] Univ Michigan, Dept Pharmacol, Med Ctr, Ann Arbor, MI 48109 USA

[4] Genom Vis, F-75014 Paris, France

来源：

CELL | 2011年 / 145卷 / 03期

关键词：

ONCOGENE-INDUCED SENESCENCE; PAPILLOMAVIRUS TYPE-16 E6; CELL-CYCLE CHECKPOINT; DNA-DAMAGE; CERVICAL-CANCER; REPLICATION STRESS; MAMMALIAN-CELLS; ORIGIN CHOICE; FRAGILE SITE; CARCINOGENESIS;

D O I：

10.1016/j.cell.2011.03.044

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：435 / 446

页数：12

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