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CRISPR-Cas13d screens identify KILR a breast cancer risk-associated lncRNA that regulates DNA replication and repair.

Wang, L.; Bitar, M.; Lu, X.; Jacquelin, S.; Nair, S.; Sivakumaran, H.; Hillman, K. M.; Kaufmann, S.; Ziegman, R.; Casciello, F.; Gowda, H.; Rosenbluh, J.; Edwards, S. L.; French, J. D.

2023-11-17 cancer biology
10.1101/2023.11.16.567471 bioRxiv
Show abstract

Long noncoding RNAs (lncRNAs) have surpassed the number of protein-coding genes, yet the majority have no known function. We previously discovered >800 lncRNAs at regions identified by breast cancer genome-wide association studies (GWAS). Here, we performed a pooled CRISPR-Cas13d RNA knockdown screen to identify which of these lncRNAs altered cell proliferation. We found that KILR, a lncRNA that functions as a tumor suppressor, safeguards breast cells against uncontrolled proliferation. The half-life of KILR is significantly reduced by the risk haplotype, revealing an alternative mechanism by which variants alter cancer risk. We showed that KILR sequesters RPA1, a subunit of the RPA complex, required for DNA replication and repair. Reduced KILR expression promotes cell proliferation by increasing the available pool of RPA1 and the speed of DNA replication. Our findings confirm lncRNAs as mediators of breast cancer risk, emphasize the need to annotate noncoding transcripts in relevant cell types when investigating GWAS variants and provide a scalable platform for mapping phenotypes associated with lncRNAs.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.