SMC1 involvement in fragile site expression

Antonio Musio, Cristina Montagna, Tullio Mariani, Manuela Tilenni, Maria Luisa Focarelli, Lorenzo Brait, Esterina Indino, Pier Alberto Benedetti, Luciana Chessa, Alberto Albertini, Thomas Reid, Paolo Vezzoni

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Common fragile sites have been involved in neoplastic transformation, although their molecular basis is still poorly understood. Here, we demonstrate that inhibition of the SMC1 by RNAi is sufficient to induce fragile site expression. By investigating normal, ATM- and ATR-deficient cell lines, we provide evidence that the contribution of SMC1 in preventing the collapse of stalled replication fork is an Atr-dependent pathway. Using a fluorescent antibody specific for γ-H2AX, we show that very rare discrete nuclear foci appear 1 and 2 h after exposure to aphidicolin and/or RNAi-SMC1, but became more numerous and distinct after longer treatment times. In this context, fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of a stalled DNA replication that lasted too long to be managed by physiological rescue acting through the Atr/Smc1 axis. We propose that in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation.

Original languageEnglish (US)
Pages (from-to)525-533
Number of pages9
JournalHuman molecular genetics
Volume14
Issue number4
DOIs
StatePublished - Feb 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Musio, A., Montagna, C., Mariani, T., Tilenni, M., Focarelli, M. L., Brait, L., Indino, E., Benedetti, P. A., Chessa, L., Albertini, A., Reid, T., & Vezzoni, P. (2005). SMC1 involvement in fragile site expression. Human molecular genetics, 14(4), 525-533. https://doi.org/10.1093/hmg/ddi049