{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T13:17:19Z","timestamp":1778591839109,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,9]]},"group-title":"Cell Biology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,9]]},"abstract":"<jats:p>\n                  Genetic mutations that drive cancer often occur in tumor suppressor proteins, including the p53 transcription factor which is altered in \u223c40-50% of cases\n                  <jats:sup>1,2<\/jats:sup>\n                  . However, current therapies fail to target most such mutations because the mutant proteins typically lack defined drug-binding pockets, and restoring the endogenous function has proven challenging. Here, we programmed CRISPR-Cas12a2, an RNA-guided nuclease with\n                  <jats:italic>trans<\/jats:italic>\n                  -nucleolytic cleavage activities\n                  <jats:sup>3,4<\/jats:sup>\n                  , to selectively kill cancer cells by targeting cancer-specific transcripts. This approach eliminates cells by inducing\n                  <jats:italic>trans<\/jats:italic>\n                  chromatin cleavage, triggering DNA damage and cell death. Unlike existing methods, RNA-guided Cas12a2 senses cellular RNA signatures to shred chromatin, enabling precise targeting of undruggable mutations. Transcript-activated chromatin shredding provides an innovative paradigm to develop precision disease treatments for undruggable targets.\n                <\/jats:p>","DOI":"10.64898\/2026.05.08.723607","type":"posted-content","created":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T14:55:12Z","timestamp":1778338512000},"source":"Crossref","is-referenced-by-count":0,"title":["Selective Elimination of TP53 Mutant Cells by Transcript-Activated Chromatin Shredding"],"prefix":"10.64898","author":[{"given":"Jingkun","family":"Zeng","sequence":"first","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA, 94158"},{"name":"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA, 94158"},{"name":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA, 94720"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhiyuan","family":"Cheng","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA, 94158"},{"name":"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA, 94158"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Huadong","family":"Chen","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jared","family":"Thompson","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kadin T.","family":"Crosby","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, Utah State University, Logan, UT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hesong","family":"Han","sequence":"additional","affiliation":[{"name":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA, 94720"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wayne","family":"Ngo","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA, 94158"},{"name":"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA, 94158"},{"name":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA, 94720"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenglong","family":"Xia","sequence":"additional","affiliation":[{"name":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA, 94720"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Rosas-Rivera","sequence":"additional","affiliation":[{"name":"Gladstone Institute of Data Science and Biotechnology, San Francisco, CA, USA, 94158"},{"name":"Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA, 94158"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min Hyung","family":"Kang","sequence":"additional","affiliation":[{"name":"Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA, 94720"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Mao","sequence":"additional","affiliation":[{"name":"Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giselle","family":"Lee","sequence":"additional","affiliation":[{"name":"The Francis Crick Institute, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John F. 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