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Human Molecular Genetics Advance Access published online on January 7, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi049
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Human Molecular Genetics © Oxford University Press 2005; all rights reserved

Article

SMC1 INVOLVEMENT IN FRAGILE SITE EXPRESSION

Antonio Musio 1*, Cristina Montagna 2, Tullio Mariani 3, Manuela Tilenni 1, Maria Luisa Focarelli 1, Lorenzo Brait 4, Esterina Indino 5, Pier Alberto Benedetti 3, Luciana Chessa 6, Alberto Albertini 1, Thomas Ried 2, and Paolo Vezzoni 1

1 Istituto di Tecnologie Biomediche, Consiglio Nazionale delle Ricerche, Via Fratelli Cervi, 93, 20090 Segrate, Milan, Italy
2 Genetics Branch, Center for Cancer Research, National Cancer Institute/NIH, Bethesda, MD 20892-8010, USA
3 Istituto per i Processi Chimico Fisici, Consiglio Nazionale delle Ricerche, 56124 Pisa, Italy
4 Istituto Nazionale Neurologico "Carlo Besta", Milan, Italy
5 Istituto Zooprofilattico Sperimentale delle Regioni Lazio e Toscana, Dipartimento Interprovinciale di Pisa, 56100 Pisa, Italy
6 Dipartimento di Medicina Sperimentale e Patologia, Università "La Sapienza", Rome, Italy

* To whom correspondence should be addressed.
Antonio Musio, E-mail: antonio.musio{at}itb.cnr.it


  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 {gamma}-H2AX, we show that very rare discrete nuclear foci appear1 and 2 hours 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 DSBs formed because of a stalled DNA replication which 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.


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