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STAG2 mutations in leukemia alter cohesin ring function, DNA damage repair, and splicing

ABSTRACT: Genome compartmentalization mediated by the cohesin complex plays an essential role in the maintenance of genome integrity and transcriptional regulation. Recurrent somatic mutations in multiple members of the cohesin complex are frequent genetic drivers in several types of cancer, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but the cellular consequences of cohesin mutations have not been determined and no therapies have been identified with selective efficacy in cohesin-mutant cancers. Using quantitative proteomics and genome-wide genetic screens in genetically engineered models of STAG2-mutant AML, we identify changes in cohesin complex composition and dependency on STAG1, DNA damage repair, master transcription factors, and RNA splicing machinery. Consistent with these findings, loss of STAG2 leads to DNA replication fork stalling and is associated with increased levels of dsDNA breaks and activation of DNA damage checkpoints, as well as aberrant splicing. Genetic or pharmacologic perturbation of DNA damage repair or splicing creates a synthetic vulnerability for cohesin-mutant cells in vitro and in vivo. Finally, STAG2 loss leads to a global reduction in cohesin binding to chromatin and expansion of super-enhancers, and mutant cohesin complexes spatially co-localize with super-enhancer enriched factors, DNA damage and splicing machinery. Our findings inform the biology of cohesins in cancer cells, and highlight novel therapeutic possibilities for cohesin-mutant malignancies.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Steven A. Carr

PROVIDER: MSV000082970 | MassIVE |

REPOSITORIES: MassIVE

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