The DNA Replication Program is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Dec 3

PMID 24289922

Citations 64

Authors

Jeannine Gerhardt

Mark J Tomishima

Nikica Zaninovic

Dilek Colak

Zi Yan

Qiansheng Zhan

Zev Rosenwaks

Samie R Jaffrey

Carl L Schildkraut

Affiliations

Soon will be listed here.

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.

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