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

Jeannine Gerhardt, Mark J. Tomishima, Nikica Zaninovic, Dilek Colak, Zi Yan, Qiansheng Zhan, Zev Rosenwaks, Samie R. Jaffrey, Carl L. Schildkraut

Research output: Contribution to journalArticle

57 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)19-31
Number of pages13
JournalMolecular Cell
Volume53
Issue number1
DOIs
StatePublished - Jan 9 2014

Fingerprint

Fragile X Syndrome
Embryonic Stem Cells
DNA Replication
Embryonic Development
Oogenesis
Replication Origin
DNA-Directed DNA Polymerase
DNA
Genes
Human Embryonic Stem Cells
Direction compound

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology
  • Medicine(all)

Cite this

The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells. / Gerhardt, Jeannine; Tomishima, Mark J.; Zaninovic, Nikica; Colak, Dilek; Yan, Zi; Zhan, Qiansheng; Rosenwaks, Zev; Jaffrey, Samie R.; Schildkraut, Carl L.

In: Molecular Cell, Vol. 53, No. 1, 09.01.2014, p. 19-31.

Research output: Contribution to journalArticle

Gerhardt, J, Tomishima, MJ, Zaninovic, N, Colak, D, Yan, Z, Zhan, Q, Rosenwaks, Z, Jaffrey, SR & Schildkraut, CL 2014, 'The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells', Molecular Cell, vol. 53, no. 1, pp. 19-31. https://doi.org/10.1016/j.molcel.2013.10.029
Gerhardt, Jeannine ; Tomishima, Mark J. ; Zaninovic, Nikica ; Colak, Dilek ; Yan, Zi ; Zhan, Qiansheng ; Rosenwaks, Zev ; Jaffrey, Samie R. ; Schildkraut, Carl L. / The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells. In: Molecular Cell. 2014 ; Vol. 53, No. 1. pp. 19-31.
@article{f75da8e836414cab841b78f4f1be6848,
title = "The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells",
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.",
author = "Jeannine Gerhardt and Tomishima, {Mark J.} and Nikica Zaninovic and Dilek Colak and Zi Yan and Qiansheng Zhan and Zev Rosenwaks and Jaffrey, {Samie R.} and Schildkraut, {Carl L.}",
year = "2014",
month = "1",
day = "9",
doi = "10.1016/j.molcel.2013.10.029",
language = "English (US)",
volume = "53",
pages = "19--31",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "1",

}

TY - JOUR

T1 - The DNA Replication Program Is Altered at the FMR1 Locus in Fragile X Embryonic Stem Cells

AU - Gerhardt, Jeannine

AU - Tomishima, Mark J.

AU - Zaninovic, Nikica

AU - Colak, Dilek

AU - Yan, Zi

AU - Zhan, Qiansheng

AU - Rosenwaks, Zev

AU - Jaffrey, Samie R.

AU - Schildkraut, Carl L.

PY - 2014/1/9

Y1 - 2014/1/9

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84892178896&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84892178896&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2013.10.029

DO - 10.1016/j.molcel.2013.10.029

M3 - Article

C2 - 24289922

AN - SCOPUS:84892178896

VL - 53

SP - 19

EP - 31

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 1

ER -