Human DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Gene.

TitleHuman DNA Helicase B as a Candidate for Unwinding Secondary CGG Repeat Structures at the Gene.
Publication TypeJournal Article
Year of Publication2018
AuthorsGuler GD, Rosenwaks Z, Gerhardt J
JournalFront Mol Neurosci
Date Published2018

The fragile X syndrome (FXS) is caused by a CGG repeat expansion at the () gene. 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, . 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 locus in unaffected and FXS cells, suggesting the formation of secondary repeat structures at the gene . 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 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 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 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 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.

Alternate JournalFront Mol Neurosci
PubMed ID29760651
PubMed Central IDPMC5936766