The lack of additional origins to help out under conditions of replication stress ... could lead to genomic instability early on in tumour development.
Batsheva Kerem, Efrat Ozeri-Galai and colleagues examined the sequence structure and replication fork progression rate at the fragile site on the long arm of chromosome 16 (FRA16C). Their sequence data and analyses using the TwistFlex program indicated that this site has several large (>400 bp) regions of AT-rich DNA, which are predicted to adopt secondary structures that impede replication fork progression. Analyses of replication progression rate at FRA16C showed that the speed of the replication forks was significantly slower (1.67 +/−0.1 kb per min versus 2.2 +/⊠0.8 kb per min for DNA sites representing the whole genome). Moreover, the frequency of slow progression forks (<1kb per min) was 25% in FRA16C, but only 8% in the rest of the genome. By studying the movement of forks that were progressing during a first round of DNA replication labelling, but which had stalled during a second round of labelling, the authors were able to identify blocked replication forks. These were rare in the whole genome (0.6% of forks), whereas five of the 100 forks analysed in FRA16C were blocked, and four of the five were clustered near the longest AT-rich region. This situation was compounded under conditions of replication stress, in which 15.6% of analysed forks in FRA16C were blocked, and these were also associated with AT-rich sequences.
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