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1.
Nat Commun ; 11(1): 1134, 2020 Feb 25.
Article in English | MEDLINE | ID: mdl-32098955

ABSTRACT

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Nat Commun ; 10(1): 4541, 2019 10 04.
Article in English | MEDLINE | ID: mdl-31586052

ABSTRACT

High-throughput CRISPR-Cas9 knockout screens using a tiling-sgRNA design permit in situ evaluation of protein domain function. Here, to facilitate de novo identification of essential protein domains from such screens, we propose ProTiler, a computational method for the robust mapping of CRISPR knockout hyper-sensitive (CKHS) regions, which refer to the protein regions associated with a strong sgRNA dropout effect in the screens. Applied to a published CRISPR tiling screen dataset, ProTiler identifies 175 CKHS regions in 83 proteins. Of these CKHS regions, more than 80% overlap with annotated Pfam domains, including all of the 15 known drug targets in the dataset. ProTiler also reveals unannotated essential domains, including the N-terminus of the SWI/SNF subunit SMARCB1, which is validated experimentally. Surprisingly, the CKHS regions are negatively correlated with phosphorylation and acetylation sites, suggesting that protein domains and post-translational modification sites have distinct sensitivities to CRISPR-Cas9 mediated amino acids loss.


Subject(s)
Computational Biology/methods , Protein Domains/genetics , Algorithms , CRISPR-Cas Systems/genetics , Cell Line, Tumor , Datasets as Topic , Gene Knockout Techniques , High-Throughput Screening Assays , Humans , Models, Genetic , Protein Processing, Post-Translational/genetics , RNA, Guide, Kinetoplastida/genetics , SMARCB1 Protein/genetics , Software
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