Volume 22, No 6, Jun 2012

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 22 Issue 6, June 2012: 973-985

ORIGINAL ARTICLES

Modulation of microRNA processing by mismatch repair protein MutLα

Guogen Mao ¹, Sanghee Lee ², Janice Ortega ¹, Liya Gu ^1,3 and Guo-Min Li ^1,2,3

¹Graduate Center for Toxicology, University of Kentucky College of Medicine, Lexington, KY 40536, USA,
²Graduate Center for Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY 40536, USA,
³Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY 40536, USA
Correspondence: Liya Gu(lgu0@uky.edu)

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.

10.1038/cr.2012.18; published online 31 January 2012

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