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

TitleThe DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells.
Publication TypeJournal Article
Year of Publication2014
AuthorsGerhardt J, Tomishima MJ, Zaninovic N, Colak D, Yan Z, Zhan Q, Rosenwaks Z, Jaffrey SR, Schildkraut CL
JournalMol Cell
Volume53
Issue1
Pagination19-31
Date Published2014 Jan 09
ISSN1097-4164
KeywordsDNA Replication, Embryonic Development, Embryonic Stem Cells, Fragile X Mental Retardation Protein, Fragile X Syndrome, Genetic Loci, Humans, Trinucleotide Repeats
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.

DOI10.1016/j.molcel.2013.10.029
Alternate JournalMol. Cell
PubMed ID24289922
PubMed Central IDPMC3920742
Grant ListR01 GM045751 / GM / NIGMS NIH HHS / United States
R01 MH080420 / MH / NIMH NIH HHS / United States
5R01-GM045751 / GM / NIGMS NIH HHS / United States
5R01MH80420 / MH / NIMH NIH HHS / United States