Replisome stalling and stabilization at CGG repeats, which are responsible for chromosomal fragility

Abstract

Expanded CGG repeats cause chromosomal fragility and hereditary neurological disorders in humans. Replication forks stall at CGG repeats in a length-dependent manner in primate cells and in yeast. Saccharomyces cerevisiae proteins Tof1 and Mrc1 facilitate replication fork progression through CGG repeats. Remarkably, the fork-stabilizing role of Mrc1 does not involve its checkpoint function. Thus, chromosomal fragility might occur when forks stalled at expanded CGG repeats escape the S-phase checkpoint.

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Figure 1: Replication fork stalling at CGG repeats in mammalian cells.
Figure 2: Genetic control of replication fork pausing at CGG repeats.
Figure 3

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Acknowledgements

We thank K. Mirkin for her help with plasmid construction, C. Freudenreich for many useful suggestions, S. Elledge (Harvard Medical School) for the plasmid with the mrc1AQ allele and J. and P. White for their generosity. Supported by the US National Institutes of Health grant GM60987 to S.M.M.

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I.V. designed and performed experiments in yeast and mammalian cells, and wrote the paper; C.F.S. performed replication studies in mammalian cells; A.A.S. performed cassettes for yeast knockouts; M.M.K. contributed to plasmid construction; S.M.M. designed experiments, supervised the whole project and wrote the paper.

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Correspondence to Sergei M Mirkin.

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Supplementary Figure 1 and Supplementary Methods (PDF 117 kb)

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Voineagu, I., Surka, C., Shishkin, A. et al. Replisome stalling and stabilization at CGG repeats, which are responsible for chromosomal fragility. Nat Struct Mol Biol 16, 226–228 (2009). https://doi.org/10.1038/nsmb.1527

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