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Molecular and Cellular Biology, October 2003, p. 7143-7151, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7143-7151.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Molecular Basis for Expression of Common and Rare Fragile Sites

Eitan Zlotorynski,1 Ayelet Rahat,1 Jennifer Skaug,2 Neta Ben-Porat,1,3 Efrat Ozeri,1 Ruth Hershberg,3 Ayala Levi,1 Stephen W. Scherer,2 Hanah Margalit,3 and Batsheva Kerem1*

Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel 91904,1 Department of Genetics, The Hospital for Sick Children, Toronto, M5G 1X8 Ontario, Canada,2 Department of Molecular Genetics and Biotechnology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel 911203

Received 6 February 2003/ Returned for modification 25 March 2003/ Accepted 2 July 2003

Fragile sites are specific loci that form gaps, constrictions, and breaks on chromosomes exposed to partial replication stress and are rearranged in tumors. Fragile sites are classified as rare or common, depending on their induction and frequency within the population. The molecular basis of rare fragile sites is associated with expanded repeats capable of adopting unusual non-B DNA structures that can perturb DNA replication. The molecular basis of common fragile sites was unknown. Fragile sites from R-bands are enriched in flexible sequences relative to nonfragile regions from the same chromosomal bands. Here we cloned FRA7E, a common fragile site mapped to a G-band, and revealed a significant difference between its flexibility and that of nonfragile regions mapped to G-bands, similar to the pattern found in R-bands. Thus, in the entire genome, flexible sequences might play a role in the mechanism of fragility. The flexible sequences are composed of interrupted runs of AT-dinucleotides, which have the potential to form secondary structures and hence can affect replication. These sequences show similarity to the AT-rich minisatellite repeats that underlie the fragility of the rare fragile sites FRA16B and FRA10B. We further demonstrate that the normal alleles of FRA16B and FRA10B span the same genomic regions as the common fragile sites FRA16C and FRA10E. Our results suggest that a shared molecular basis, conferred by sequences with a potential to form secondary structures that can perturb replication, may underlie the fragility of rare fragile sites harboring AT-rich minisatellite repeats and aphidicolin-induced common fragile sites.

* Corresponding author. Mailing address: Department of Genetics, The Life Sciences Institute, Edmond Safra Campus, Givat Ram, Hebrew University, Jerusalem, Israel 91904. Phone: 972-2-6585689. Fax: 972-2-6586975. E-mail: kerem{at}cc.huji.ac.il.

Molecular and Cellular Biology, October 2003, p. 7143-7151, Vol. 23, No. 20
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.20.7143-7151.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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