Abstract
MicroRNAs (miRNAs) are critical post-transcriptional regulators and are derived from hairpin-shaped primary transcripts via a series of processing steps. However, how the production of individual miRNAs is regulated remains largely unknown. Similarly, loss or overexpression of the key mismatch repair protein MutLα (MLH1-PMS2 heterodimer) leads to genome instability and tumorigenesis, but the mechanisms controlling MutLα expression are unknown. Here we demonstrate in vitro and in vivo that MLH1 and miR-422a participate in a feedback loop that regulates the level of both molecules. Using a defined in-vitro miRNA processing system, we show that MutLα stimulates the conversion of pri-miR-422a to pre-miR-422a, as well as the processing of other miRNAs tested, implicating MutLα as a general stimulating factor for miRNA biogenesis. This newly identified MutLα function requires its ATPase and pri-miRNA binding activities. In contrast, miR-422a downregulates MutLα levels by suppressing MLH1 expression through base pairing with the MLH1 3′-untranslated region. A model depicting this feedback mechanism is discussed.
Original language | English (US) |
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Pages (from-to) | 973-985 |
Number of pages | 13 |
Journal | Cell Research |
Volume | 22 |
Issue number | 6 |
DOIs | |
State | Published - Jun 2012 |
Keywords
- 3′-UTR
- DGCR8
- Drosha
- MLH1
- MutLα
- miRNA
- mismatch repair
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology