Oncogenes induce genotoxic stress by mitotic processing of unusual replication intermediates

Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E an...

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Vydáno v:The Journal of cell biology Ročník 200; číslo 6; s. 699
Hlavní autoři: Neelsen, Kai J, Zanini, Isabella M Y, Herrador, Raquel, Lopes, Massimo
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 18.03.2013
Témata:
CDC2 Protein Kinase - genetics
CDC2 Protein Kinase - metabolism
cdc25 Phosphatases - genetics
cdc25 Phosphatases - metabolism
Cell Line, Tumor
Chromosome Breakage
Cyclin E - genetics
Cyclin E - metabolism
DNA Replication
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endonucleases - genetics
Endonucleases - metabolism
G2 Phase
Humans
Mitosis
Oncogenes
ISSN:1540-8140, 1540-8140
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Shrnutí:Oncogene-induced DNA replication stress activates the DNA damage response (DDR), a crucial anticancer barrier. DDR inactivation in these conditions promotes genome instability and tumor progression, but the underlying molecular mechanisms are elusive. We found that overexpression of both Cyclin E and Cdc25A rapidly slowed down replication forks and induced fork reversal, suggestive of increased topological stress. Surprisingly, these phenotypes, per se, are neither associated with chromosomal breakage nor with significant DDR activation. Oncogene-induced DNA breakage and DDR activation instead occurred upon persistent G2/M arrest or, in a checkpoint-defective context, upon premature CDK1 activation. Depletion of MUS81, a cell cycle-regulated nuclease, markedly limited chromosomal breakage and led to further accumulation of reversed forks. We propose that nucleolytic processing of unusual replication intermediates mediates oncogene-induced genotoxicity and that limiting such processing to mitosis is a central anti-tumorigenic function of the DNA damage checkpoints.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:1540-8140
1540-8140
DOI:10.1083/jcb.201212058