Replication of a common fragile site, FRA3B, occurs late in S phase and is delayed further upon induction: Implications for the mechanism of fragile site induction

Michelle M. Le Beau, Feyruz V. Rassool, Mary E. Neilly, Rafael Espinosa, Thomas W. Glover, David I. Smith, Timothy W. McKeithan

Research output: Contribution to journalArticle

175 Scopus citations

Abstract

The FRA3B at 3p14.2 is the most highly expressed of the common fragile sites observed when DNA replication is perturbed by aphidicolin or folate stress. The molecular basis for chromosome fragility at FRA3B is unknown. In contrast to the rare fragile sites, including FRAXA, no repeat motifs, such as trinucleotide repeats, have been identified within FRA3B. Several lines of evidence suggest that fragile sites are regions of DNA whose replication is unusually sensitive to interference. We have used fluorescence in situ hybridization to determine the relative timing of replication of FRA3B sequences. Our studies revealed that FRA3B sequences are late replicating. Exposure to aphidicolin, an inhibitor of both DNA polymerase α and δ, results in a reproducible delay in the timing of replication, and some cells enter G2 without having completed replication of FRA3B sequences. Our results support a model in which common fragile sites are sequences that initiate replication late in S phase or are slow to replicate, and the chromosomal breaks and gaps observed in metaphase cells are due to unreplicated DNA.

Original languageEnglish (US)
Pages (from-to)755-761
Number of pages7
JournalHuman molecular genetics
Volume7
Issue number4
DOIs
StatePublished - Apr 1 1998

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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