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Mol Cell. 2014 Jan 9;53(1):19-31. doi: 10.1016/j.molcel.2013.10.029. Epub 2013 Nov 27.

The DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells.

Author information

1
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: jeannine.gerhardt@gmail.com.
2
SKI Stem Cell Research Facility, Sloan-Kettering Institute, New York, NY 10065, USA.
3
Center for Reproductive Medicine and Infertility, Weill Cornell Medical College, New York, NY 10065, USA.
4
Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA.
5
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
6
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: carl.schildkraut@einstein.yu.edu.

Abstract

Fragile X syndrome (FXS) is caused by a CGG repeat expansion in the FMR1 gene that appears to occur during oogenesis and during early embryogenesis. One model proposes that repeat instability depends on the replication fork direction through the repeats such that (CNG)n hairpin-like structures form, causing DNA polymerase to stall and slip. Examining DNA replication fork progression on single DNA molecules at the endogenous FMR1 locus revealed that replication forks stall at CGG repeats in human cells. Furthermore, replication profiles of FXS human embryonic stem cells (hESCs) compared to nonaffected hESCs showed that fork direction through the repeats is altered at the FMR1 locus in FXS hESCs, such that predominantly the CCG strand serves as the lagging-strand template. This is due to the absence of replication initiation that would typically occur upstream of FMR1, suggesting that altered replication origin usage combined with fork stalling promotes repeat instability during early embryonic development.

PMID:
24289922
PMCID:
PMC3920742
DOI:
10.1016/j.molcel.2013.10.029
[Indexed for MEDLINE]
Free PMC Article

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