AI Article Synopsis

  • Researchers developed a CRISPR screening method that uses time-controlled Cas9 mutagenesis to study gene regulation without affecting cell health.* -
  • The study focused on the transcription factor MYC, revealing a crucial protein called AKIRIN2 that is necessary for the nuclear import and degradation of proteins, like MYC.* -
  • AKIRIN2 plays a key role during cell division by ensuring proteasomes are imported into daughter nuclei, and its absence leads to an excess of nuclear proteins, highlighting a new pathway in vertebrate cellular regulation.*

Article Abstract

Protein expression and turnover are controlled through a complex interplay of transcriptional, post-transcriptional and post-translational mechanisms to enable spatial and temporal regulation of cellular processes. To systematically elucidate such gene regulatory networks, we developed a CRISPR screening assay based on time-controlled Cas9 mutagenesis, intracellular immunostaining and fluorescence-activated cell sorting that enables the identification of regulatory factors independent of their effects on cellular fitness. We pioneered this approach by systematically probing the regulation of the transcription factor MYC, a master regulator of cell growth. Our screens uncover a highly conserved protein, AKIRIN2, that is essentially required for nuclear protein degradation. We found that AKIRIN2 forms homodimers that directly bind to fully assembled 20S proteasomes to mediate their nuclear import. During mitosis, proteasomes are excluded from condensing chromatin and re-imported into newly formed daughter nuclei in a highly dynamic, AKIRIN2-dependent process. Cells undergoing mitosis in the absence of AKIRIN2 become devoid of nuclear proteasomes, rapidly causing accumulation of MYC and other nuclear proteins. Collectively, our study reveals a dedicated pathway controlling the nuclear import of proteasomes in vertebrates and establishes a scalable approach to decipher regulators in essential cellular processes.

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http://dx.doi.org/10.1038/s41586-021-04035-8DOI Listing

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