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Human Molecular Genetics Advance Access originally published online on January 7, 2005
Human Molecular Genetics 2005 14(4):525-533; doi:10.1093/hmg/ddi049
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Human Molecular Genetics, Vol. 14, No. 4 © Oxford University Press 2005; all rights reserved

SMC1 involvement in fragile site expression

Antonio Musio1,*, Cristina Montagna2, Tullio Mariani3, Manuela Tilenni1, Maria Luisa Focarelli1, Lorenzo Brait4, Esterina Indino5, Pier Alberto Benedetti3, Luciana Chessa6, Alberto Albertini1, Thomas Ried2 and Paolo Vezzoni1

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

Received October 7, 2004; Revised November 29, 2004; Accepted December 21, 2004

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 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.

* To whom correspondence should be addressed. Tel: +39 0226422632; Fax: +39 0226422660; Email: antonio.musio{at}itb.cnr.it


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