Cargando…

Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene

The fragile X syndrome (FXS) is caused by a CGG repeat expansion at the fragile X mental retardation (FMR1) gene. FMR1 alleles with more than 200 CGG repeats bear chromosomal fragility when cells experience folate deficiency. CGG repeats were reported to be able to form secondary structures, such as...

Descripción completa

Detalles Bibliográficos
Autores principales: Guler, Gulfem D., Rosenwaks, Zev, Gerhardt, Jeannine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936766/
https://www.ncbi.nlm.nih.gov/pubmed/29760651
http://dx.doi.org/10.3389/fnmol.2018.00138
_version_ 1783320513882357760
author Guler, Gulfem D.
Rosenwaks, Zev
Gerhardt, Jeannine
author_facet Guler, Gulfem D.
Rosenwaks, Zev
Gerhardt, Jeannine
author_sort Guler, Gulfem D.
collection PubMed
description The fragile X syndrome (FXS) is caused by a CGG repeat expansion at the fragile X mental retardation (FMR1) gene. FMR1 alleles with more than 200 CGG repeats bear chromosomal fragility when cells experience folate deficiency. CGG repeats were reported to be able to form secondary structures, such as hairpins, in vitro. When such secondary structures are formed, repeats can lead to replication fork stalling even in the absence of any additional perturbation. Indeed, it was recently shown that the replication forks stall at the endogenous FMR1 locus in unaffected and FXS cells, suggesting the formation of secondary repeat structures at the FMR1 gene in vivo. If not dealt with properly replication fork stalling can lead to polymerase slippage and repeat expansion as well as fragile site expression. Despite the presence of repeat structures at the FMR1 locus, chromosomal fragility is only expressed under replicative stress suggesting the existence of potential molecular mechanisms that help the replication fork progress through these repeat regions. DNA helicases are known to aid replication forks progress through repetitive DNA sequences. Yet, the identity of the DNA helicase(s) responsible for unwinding the CGG repeats at FMR1 locus is not known. We found that the human DNA helicase B (HDHB) may provide an answer for this question. We used chromatin-immunoprecipitation assay to study the FMR1 region and common fragile sites (CFS), and asked whether HDHB localizes at replication forks stalled at repetitive regions even in unperturbed cells. HDHB was strongly enriched in S-phase at the repetitive DNA at CFS and FMR1 gene but not in the flanking regions. Taken together, these results suggest that HDHB functions in preventing or repairing stalled replication forks that arise in repeat-rich regions even in unperturbed cells. Furthermore, we discuss the importance and potential role of HDHB and other helicases in the resolution of secondary CGG repeat structures.
format Online
Article
Text
id pubmed-5936766
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-59367662018-05-14 Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene Guler, Gulfem D. Rosenwaks, Zev Gerhardt, Jeannine Front Mol Neurosci Neuroscience The fragile X syndrome (FXS) is caused by a CGG repeat expansion at the fragile X mental retardation (FMR1) gene. FMR1 alleles with more than 200 CGG repeats bear chromosomal fragility when cells experience folate deficiency. CGG repeats were reported to be able to form secondary structures, such as hairpins, in vitro. When such secondary structures are formed, repeats can lead to replication fork stalling even in the absence of any additional perturbation. Indeed, it was recently shown that the replication forks stall at the endogenous FMR1 locus in unaffected and FXS cells, suggesting the formation of secondary repeat structures at the FMR1 gene in vivo. If not dealt with properly replication fork stalling can lead to polymerase slippage and repeat expansion as well as fragile site expression. Despite the presence of repeat structures at the FMR1 locus, chromosomal fragility is only expressed under replicative stress suggesting the existence of potential molecular mechanisms that help the replication fork progress through these repeat regions. DNA helicases are known to aid replication forks progress through repetitive DNA sequences. Yet, the identity of the DNA helicase(s) responsible for unwinding the CGG repeats at FMR1 locus is not known. We found that the human DNA helicase B (HDHB) may provide an answer for this question. We used chromatin-immunoprecipitation assay to study the FMR1 region and common fragile sites (CFS), and asked whether HDHB localizes at replication forks stalled at repetitive regions even in unperturbed cells. HDHB was strongly enriched in S-phase at the repetitive DNA at CFS and FMR1 gene but not in the flanking regions. Taken together, these results suggest that HDHB functions in preventing or repairing stalled replication forks that arise in repeat-rich regions even in unperturbed cells. Furthermore, we discuss the importance and potential role of HDHB and other helicases in the resolution of secondary CGG repeat structures. Frontiers Media S.A. 2018-04-30 /pmc/articles/PMC5936766/ /pubmed/29760651 http://dx.doi.org/10.3389/fnmol.2018.00138 Text en Copyright © 2018 Guler, Rosenwaks and Gerhardt. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Guler, Gulfem D.
Rosenwaks, Zev
Gerhardt, Jeannine
Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene
title Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene
title_full Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene
title_fullStr Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene
title_full_unstemmed Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene
title_short Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Fragile X Mental Retardation Gene
title_sort human dna helicase b as a candidate for unwinding secondary cgg repeat structures at the fragile x mental retardation gene
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5936766/
https://www.ncbi.nlm.nih.gov/pubmed/29760651
http://dx.doi.org/10.3389/fnmol.2018.00138
work_keys_str_mv AT gulergulfemd humandnahelicasebasacandidateforunwindingsecondarycggrepeatstructuresatthefragilexmentalretardationgene
AT rosenwakszev humandnahelicasebasacandidateforunwindingsecondarycggrepeatstructuresatthefragilexmentalretardationgene
AT gerhardtjeannine humandnahelicasebasacandidateforunwindingsecondarycggrepeatstructuresatthefragilexmentalretardationgene