SMC1 involvement in fragile site expression

Year: 2005

Authors: Musio A., Montagna C., Mariani T., Tilenni M., Focarelli M.L., Brait L., Indino E., Benedetti P.A., Chessa L., Albertini A., Ried T., Vezzoni P.

Autors Affiliation: CNR, Ist Tecnol Biomed, I-20090 Milan, Italy; NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA; CNR, Ist Proc Chim Fis, I-56124 Pisa, Italy; Ist Nazl Neurol Carlo Besta, Milan, Italy Ist Zooprofilatt Sperimentale Reg Lazio & Toscana, Dipartimento Interprov Pisa, I-56100 Pisa, Italy Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, I-00185 Rome, Italy

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 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.

Journal/Review: HUMAN MOLECULAR GENETICS

Volume: 14 (4)      Pages from: 525  to: 533

DOI: 10.1093/hmg/ddi049

ImpactFactor: 7.764
Citations: 81
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