Interrogation of cancer gene dependencies reveals paralog interactions of autosome and sex chromosome-encoded genes

• DOI: 10.1016/j.celrep.2022.110636
• Publication Date: 2022-04-13T04:13:59Z
• Authors: Anna Köferle; Andreas Schlattl; Alexandra Hörmann; Venu Thatikonda; Alexandra Popa; Fiona Spreitzer; Madhwesh C. Ravic...; Verena Supper; Sarah Oberndorfer; Teresa Puchner; Corinna Wieshofer; Maja Corcokovic; Christoph Reiser; Simon Wöhrle; Johannes Popow; Mark Pearson; Javier Martinez; Stefan Weitzer; Barbara Mair; Ralph A. Neumüller
• Keywords: Male; 0301 basic medicine; Sex Chromosomes; X Chromosome; RNA-Binding Proteins; Oncogenes; 3. Good health; DEAD-box RNA Helicases; DNA-Binding Proteins; Minor Histocompatibility Antigens; 03 medical and health sciences; Neoplasms; Y Chromosome; Humans

Genetic networks are characterized by extensive buffering. During tumor evolution, disruption of functional redundancies can create de novo vulnerabilities that specific to cancer cells. Here, we systematically search for cancer-relevant paralog interactions using CRISPR screens and publicly available loss-of-function datasets. Our analysis reveals >2,000 candidate dependencies, several which validate experimentally, including CSTF2-CSTF2T, DNAJC15-DNAJC19, FAM50A-FAM50B, RPP25-RPP25L. We provide evidence RPP25L physically functionally compensate the absence RPP25 as a member RNase P/MRP complexes in tRNA processing. also unexpected between sex chromosome genes. show chrX- chrY-encoded paralogs, such ZFX-ZFY, DDX3X-DDX3Y, EIF1AX-EIF1AY, linked. Tumor cell lines from male patients with loss Y become dependent on chrX-encoded gene. propose targeting paralogs general therapeutic strategy human tumors have lost chromosome.