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The DEAH helicase RHAU is essential for embryogenesis and hematopoiesis

Lai, Ching Janice. The DEAH helicase RHAU is essential for embryogenesis and hematopoiesis. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_9914

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Abstract

The DEAH helicase RHAU (alias DHX36, G4R1) was recently identified as a shuttle protein localized mainly in the nucleus. It is the only helicase shown to have G4-RNA resolvase activity and the major source of G4-DNA resolvase activity in HeLa cell lysate. Its ablation reduces the proliferation rate of various human cell lines in culture. The Human Gene Atlas database (GNF, Novartis) shows ubiquitous expression of RHAU, with prominently elevated levels in lymphoid and CD34+ bone marrow cells, suggesting a potential role in hematopoiesis. To investigate the biological role of RHAU, we generated mice in which the RHAU gene was targeted conventionally or specifically in the hematopoietic system.
Conventional RHAU ablation caused embryonic lethality before 7.5 days after fertilization but without disturbing embryo implantation, suggesting a fundamental role for RHAU in early development (gastrulation).
Because conventional RHAU-ablation caused embryonic lethality, we then targeted the RHAU gene specifically in the hematopoiesis system. To achieve this we used vav1-iCre system, in which iCre gene (an optimized variant of Cre recombinase) was expressed under the control of vav1 oncogen promoter that was active solely in the hematopoietic system. Results showed that RHAU-ablation in the hematopoietic system strongly affected the process of hematopoiesis in a lineage- and stage-specific manner. Notably, RHAU ablation caused hemolytic anemia and strong impairment of lymphoid cell differentiation at early its stages.
Finally, by micro-array analysis we examined the effect of RHAU ablation on the change of transcriptome in proerythroblasts. We found that within a group of genes involved in cell death and cell cycle regulation, RHAU-ablation deregulated those genes that contained G-quadruplex motifs in their promoter regions. This result suggests that RHAU plays a role in the regulation of gene expression through involving its G4 resolvase activity.
Advisors:Skoda, Radek C.
Committee Members:Matthias, Patrick D. and Hynes, Nancy
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Experimental Hematology (Skoda)
Item Type:Thesis
Thesis no:9914
Bibsysno:Link to catalogue
Number of Pages:108 S.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:49
Deposited On:04 Jul 2012 14:46

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