PUMILIO competes with AUF1 to control DICER1 RNA levels and miRNA processing

Author:

Rajasekaran Swetha12,Khan Eshan12,Ching Samuel R3,Khan Misbah12,Siddiqui Jalal K12,Gradia Daniela F45,Lin Chenyu12ORCID,Bouley Stephanie J3,Mercadante Dayna L6,Manning Amity L67,Gerber André P4ORCID,Walker James A389,Miles Wayne O12ORCID

Affiliation:

1. Department of Cancer Biology and Genetics, The Ohio State University , 460 West 12th Avenue , Columbus , OH 43210 , USA

2. The Ohio State University Comprehensive Cancer Center, The Ohio State University , 460 West 12th Avenue , Columbus , OH 43210 , USA

3. Center for Genomic Medicine, Massachusetts General Hospital , Boston , MA 02114, USA

4. Department of Microbial Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey , Guildford , Surrey GU2 7XH, UK

5. Department of Genetics, Federal University of Parana , Curitiba , Brazil

6. Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, 100 Institute Road , Worcester , MA 01609, USA

7. Department of Biology and Biotechnology, Worcester Polytechnic Institute, 100 Institute Road , Worcester , MA 01609, USA

8. Department of Neurology, Massachusetts General Hospital, Harvard Medical School , Boston , USA

9. Cancer Program, Broad Institute of MIT and Harvard , Cambridge , MA 02142, USA

Abstract

Abstract DICER1 syndrome is a cancer pre-disposition disorder caused by mutations that disrupt the function of DICER1 in miRNA processing. Studying the molecular, cellular and oncogenic effects of these mutations can reveal novel mechanisms that control cell homeostasis and tumor biology. Here, we conduct the first analysis of pathogenic DICER1 syndrome allele from the DICER1 3′UTR. We find that the DICER1 syndrome allele, rs1252940486, abolishes interaction with the PUMILIO RNA binding protein with the DICER1 3′UTR, resulting in the degradation of the DICER1 mRNA by AUF1. This single mutational event leads to diminished DICER1 mRNA and protein levels, and widespread reprogramming of miRNA networks. The in-depth characterization of the rs1252940486 DICER1 allele, reveals important post-transcriptional regulatory events that control DICER1 levels.

Funder

National Cancer Institute

American Cancer Society

BBSRC

Royal Society Wolfson

CNPq Science

NCI

Publisher

Oxford University Press (OUP)

Subject

Genetics

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