Regulation of gene expression by the BLM helicase correlates with the presence of G-quadruplex DNA motifs.

Abstract

Bloom syndrome is a rare autosomal recessive disorder characterized by genetic instability and cancer predisposition, and caused by mutations in the gene encoding the Bloom syndrome, RecQ helicase-like (BLM) protein. To determine whether altered gene expression might be responsible for pathological features of Bloom syndrome, we analyzed mRNA and microRNA (miRNA) expression in fibroblasts from individuals with Bloom syndrome and in BLM-depleted control fibroblasts. We identified mRNA and miRNA expression differences in Bloom syndrome patient and BLM-depleted cells. Differentially expressed mRNAs are connected with cell proliferation, survival, and molecular mechanisms of cancer, and differentially expressed miRNAs target genes involved in cancer and in immune function. These and additional altered functions or pathways may contribute to the proportional dwarfism, elevated cancer risk, immune dysfunction, and other features observed in Bloom syndrome individuals. BLM binds to G-quadruplex (G4) DNA, and G4 motifs were enriched at transcription start sites (TSS) and especially within first introns (false discovery rate ≤ 0.001) of differentially expressed mRNAs in Bloom syndrome compared with normal cells, suggesting that G-quadruplex structures formed at these motifs are physiologic targets for BLM. These results identify a network of mRNAs and miRNAs that may drive the pathogenesis of Bloom syndrome.

• Authors: Giang Huong Nguyen, Weiliang Tang, Ana I Robles, Richard P Beyer, Lucas T Gray, Judith A Welsh, Aaron J Schetter, Kensuke Kumamoto, Xin Wei Wang, Ian D Hickson, Nancy Maizels, Raymond J Monnat Jr, Curtis C Harris
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 27 Pg. 9905-10 (Jul 08 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 24958861 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• DNA
• Bloom syndrome protein
• RecQ Helicases

Topics

• Bloom Syndrome (genetics)
• Cells, Cultured
• DNA (chemistry)
• G-Quadruplexes
• Gene Expression Profiling
• Gene Expression Regulation, Enzymologic
• Humans
• RNA, Messenger (genetics)
• RecQ Helicases (genetics)