Failure of Origin Activation in Response to Fork Stalling Leads to Chromosomal Instability at Fragile Sites

Efrat Ozeri-Galai, Ronald Lebofsky, Ayelet Rahat, Assaf C. Bester, Aaron Bensimon, Batsheva Kerem*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

Perturbed DNA replication in early stages of cancer development induces chromosomal instability preferentially at fragile sites. However, the molecular basis for this instability is unknown. Here, we show that even under normal growth conditions, replication fork progression along the fragile site, FRA16C, is slow and forks frequently stall at AT-rich sequences, leading to activation of additional origins to enable replication completion. Under mild replication stress, the frequency of stalling at AT-rich sequences is further increased. Strikingly, unlike in the entire genome, in the FRA16C region additional origins are not activated, suggesting that all potential origins are already activated under normal conditions. Thus, the basis for FRA16C fragility is replication fork stalling at AT-rich sequences and inability to activate additional origins under replication stress. Our results provide a mechanism explaining the replication stress sensitivity of fragile sites and thus, the basis for genomic instability during early stages of cancer development.

Original languageAmerican English
Pages (from-to)122-131
Number of pages10
JournalMolecular Cell
Volume43
Issue number1
DOIs
StatePublished - 8 Jul 2011

Bibliographical note

Funding Information:
This project was partially supported by the Israel Science Foundation, the Association International Cancer Research, and the Israel Cancer Association to B.K. and by the High Council for Scientific and Technologies Cooperation between France-Israel, Research Network in Human Genetics to A.B. and B.K. The authors wish to thank Shlomo Yitzchaik for assistance in slide preparation, Steve Scherer for providing the BAC clones, and Michal Tur-Sinai Irony, Dan Sarni, and Yifat Oren for assistance with experiments and finalizing the manuscript.

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