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HMGA1 zebrafish co-orthologue hmga1b can modulate p53-dependent cellular responses but is unable to control the alternative splicing of psen1

View ORCID ProfileSeyed Hani Moussavi Nik, View ORCID ProfileMorgan Newman, View ORCID ProfileAmanda Lumsden, Tanya Jayne, View ORCID ProfileMichael Lardelli
doi: https://doi.org/10.1101/241927
Seyed Hani Moussavi Nik
1Alzheimer’s Disease Genetics Laboratory, Center for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
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  • For correspondence: Seyyed.moussavinik@adelaide.edu.au
Morgan Newman
1Alzheimer’s Disease Genetics Laboratory, Center for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
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Amanda Lumsden
2College of Medicine and Public Health, and Center for Neuroscience, Flinders University, Adelaide, South Australia, Australia
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Tanya Jayne
1Alzheimer’s Disease Genetics Laboratory, Center for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
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Michael Lardelli
1Alzheimer’s Disease Genetics Laboratory, Center for Molecular Pathology, School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia
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ABSTRACT

The HIGH MOBILITY GROUP AT-HOOK 1 (HMGA1) family of chromatin-binding proteins plays important roles in cellular responses to low oxygen. HMGA1 proteins regulate gene activity both in the nucleus and within mitochondria. They are expressed mainly during embryogenesis and their upregulation in cancerous cells indicates poor prognosis. The human HMGA1a isoform is upregulated under hypoxia via oxidative stress-dependent signalling and can then bind nascent transcripts of the familial Alzheimer’s disease gene PSEN2 to regulate alternative splicing to produce the truncated PSEN2 protein isoform PS2V. Zebrafish where hmga1a expression is induced by hypoxia to control splicing of the psen1 gene to produce the PS2V-equivalent isoform PS1IV. Zebrafish possess a second gene with apparent HMGA1 orthology, hmga1b. Here we investigate the predicted structure of Hmga1b protein and demonstrate it to be co-orthologous to human HMGA1 and most similar in structure to human isoform HMGA1c. We show that forced over-expression of either hmga1a or hmga1b mRNA can suppress the action of the cytotoxin hydroxyurea in stimulating cell death and transcription of the genes mdm2 and cdkn1a that, in humans, are controlled by p53. Our experimental data support an important role for HMGA1 proteins in modulation of p53-dependent responses and illuminate the evolutionary subfunctionalisation.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted January 02, 2018.
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HMGA1 zebrafish co-orthologue hmga1b can modulate p53-dependent cellular responses but is unable to control the alternative splicing of psen1
Seyed Hani Moussavi Nik, Morgan Newman, Amanda Lumsden, Tanya Jayne, Michael Lardelli
bioRxiv 241927; doi: https://doi.org/10.1101/241927
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HMGA1 zebrafish co-orthologue hmga1b can modulate p53-dependent cellular responses but is unable to control the alternative splicing of psen1
Seyed Hani Moussavi Nik, Morgan Newman, Amanda Lumsden, Tanya Jayne, Michael Lardelli
bioRxiv 241927; doi: https://doi.org/10.1101/241927

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