{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE328nnn/GSE328796/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE328796"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Targeting Cyclin K-CDK12 Synergizes with ATR Inhibition by Limiting RPA Chromatin Loading in Triple-Negative Breast Cancer [ChIP-seq]","description":"Cyclin K-CDK12 inhibition has emerged as a promising therapeutic strategy to induce homologous recombination deficiency (HRD). However, clinical and genomic studies have not clearly linked CDK12 inactivation to HRD. Here, we demonstrate that cyclin K-CDK12 depletion drives a replication stress (RS)-associated vulnerability through RPA regulation. A DNA damage response-focused CRISPR screen identified DNA replication factors and ATR activators as top sensitizers to cyclin K degradation. Consistently, cyclin K-CDK12 depletion synergized with ATR inhibition in triple-negative breast cancer (TNBC) models. Cyclin K degradation reduces RPA chromatin loading and impairs ATR activation, compromising cellular tolerance to RS and increasing susceptibility to ATR inhibition. We show that CDK12-mediated phosphorylation of CDC5L is required for RPA chromatin loading and mediates resistance to combined cyclin K and ATR depletion. Our findings identify cyclin K-CDK12 as a critical regulator of RPA dynamics and support its inhibition as rational therapy for RS-high tumors, including TNBC.","dates":{"publication":"2026/04/27"},"accession":"GSE328796","cross_references":{"GSM":["GSM9689860","GSM9689861","GSM9689857","GSM9689856","GSM9689859","GSM9689858"],"GPL":["24676"],"GSE":["328796"],"taxon":["Homo sapiens"]}}