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SIRT1 modulates miRNA processing defects in p53-mutated human keratinocytes.
Katharine J Herbert1, Anthony L Cook1, Elizabeth T Snow1
1School of Health Sciences, University of Tasmania, Launceston, TAS 7250, Australia.
Journal of Dermatological Science
|February 20, 2014
Summary
p53 mutations impair microRNA maturation in keratinocytes. SIRT1 (NAD-dependent deacetylase) works with p53 to regulate microRNA processing and biogenesis.
Area of Science:
- Cellular biology
- Molecular genetics
- Biochemistry
Background:
- The p53, SIRT1 (NAD-dependent deacetylase), and miR-34a feedback loop regulates SIRT1 expression and p53 responses.
- p53 influences microRNA processing and maturation beyond its role in genotoxic stress responses.
Purpose of the Study:
- To investigate the interplay between p53, SIRT1, and miR-34a.
- To determine how p53 and SIRT1 affect microRNA biogenesis and maturation in keratinocytes.
Main Methods:
- RNA interference (RNAi) and small molecule inhibitors modulated SIRT1 and p53.
- Quantitative reverse transcription PCR (qRT-PCR) analyzed microRNA and mRNA levels.
- Immunoblotting assessed protein expression.
Main Results:
- p53 suppression reduced mature miR-34a; SIRT1 ablation decreased pri-miR-34a.
- Inhibiting SIRT1 with p53 suppression increased pri-miR-34a but decreased mature miR-34a.
- p53-regulated microRNAs (miR-16-1/15, miR-145, miR-107) failed to mature under these conditions.
- p53-mutated HaCaT cells showed altered microRNA precursor and mature levels compared to primary NHEK cells.
Conclusions:
- p53 mutations disrupt efficient microRNA biogenesis in keratinocytes.
- SIRT1 collaborates with p53 in the microRNA biogenesis pathway.
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