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A genome-wide phenotypic CRISPR/Cas9 screen identifies novel regulators of PARK2 level and mitophagy priming

Potting, Christoph and Sailer, Andreas and Helliwell, Stephen (2017) A genome-wide phenotypic CRISPR/Cas9 screen identifies novel regulators of PARK2 level and mitophagy priming. Proceedings of the National Academy of Sciences of the United States of America PNAS. (10.107). pp. 1-10. ISSN 1091-6490; 0027-8424

Abstract

PARKIN, an E3 ligasemutated in familial Parkinson’s disease, promotes mitophagy by ubiquitinating mitochondrial proteins for efficient engagement of the autophagy machinery. Specifically, PARKIN- synthesized ubiquitin chains represent targets for the PINK1 kinase generating phosphoS65-ubiquitin (pUb),which constitutes the mitoph- agy signal. Physiological regulation of PARKIN abundance, however, and the impact on pUb accumulation are poorly understood. Using cells designed to discover physiological regulators of PARKIN abun- dance, we performed a pooled genome-wide CRISPR/Cas9 knockout screen. Testing identified genes individually resulted in a list of 53 positive and negative regulators. A transcriptional repressor net- work including THAP11 was identified and negatively regulates en- dogenous PARKIN abundance. RNAseq analysis revealed the PARKIN-encoding locus as a prime THAP11 target, and THAP11 CRISPR knockout in multiple cell types enhanced pUb accumulation. Thus, our work demonstrates the critical role of PARKIN abundance, identifies regulating genes, and reveals a link between transcriptional repres- sion andmitophagy,which is also apparent in human induced plurip- otent stem cell-derived neurons, a disease-relevant cell type.
PARKIN

Item Type: Article
Date Deposited: 19 Jan 2018 00:45
Last Modified: 19 Jan 2018 00:45
URI: https://oak.novartis.com/id/eprint/32378

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