Abstract
Abstract The DNA damage response (DDR) ensures error-free genome replication and transcription, but is often disrupted in cancer. We developed DDRAM, a multilayered map of DDR derived from our own high-throughput physical interaction screen as well as genome, transcriptome, and proteome datasets from published sources. DDRAM organizes 328 genes into 41 hierarchical pathways. We identify 55 (17%) novel DDR genes with functions distributed across various pathways, and novel and more specific roles for 153 (47%) of established DDR genes. We perform epistasis mapping to support novel pathway assignments of FOXK1 in nucleotide metabolism and XRCC3 in the Fanconi anemia pathway. Using quantitative imaging of a fluorescent probe, in some cases confirmed by epistasis mapping, we experimentally validate members of the Short Patch Base Excision Repair pathway over a time course, revealing a more complete model of poly(ADP-ribose)-dependent recruitment to sites of DNA damage. Citation Format: Anton Kratz, Minkyu Kim, Fan Zheng, Christopher A. Koczor, Samson Fong, Jianfeng Li, Robert W. Sobol, Nevan Krogan, Trey Ideker. A multiscale map of DNA damage response in human cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2078.
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