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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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Splicing modulators impair DNA damage response and induce killing of cohesin-mutant MDS/AML

Project description:Splicing modulation is a promising treatment strategy pursued to date only in splicing-factor mutant cancers; however, its therapeutic potential is poorly understood outside of this context. Like splicing factors, genes encoding components of the cohesin complex are frequently mutated in cancer and are associated with poor outcomes in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, we show that cohesin mutations are biomarkers of sensitivity to drugs targeting splicing-factor SF3B1 (H3B-8800 and E-7107) and identify drug-induced alterations in splicing of DNA repair genes as the mechanism underlying this sensitivity. We demonstrate that treatment of cohesin-mutant cells with SF3B1 modulators results in impaired DNA damage response, accumulation of DNA damage, and increased sensitivity to a panel of chemotherapeutic agents in vitro and in vivo. Our findings expand the potential therapeutic benefits of SF3B1 splicing modulators to include cohesin-mutant MDS/AML.

2023-06-30 | GSE198518 | GEO

Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML

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Inactivation of the Budding Yeast Cohesin Loader Scc2 alters Gene Expression both Globally and in Response to a Single DNA Double Strand Break [ChIP-seq]

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2014-04-03 | GSE54741 | GEO

Microarray analysis comparing yeast Eco1 mutant W216G to mutants of FOB1 and RAD61

2014-04-03 | E-GEOD-54741 | biostudies-arrayexpress

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2020-03-03 | GSE131558 | GEO

Inactivation of the Budding Yeast Cohesin Loader Scc2 alters Gene Expression both Globally and in Response to a Single DNA Double Strand Break

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Cohesin profiling at DSBs

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2012-01-01 | E-TABM-1164 | biostudies-arrayexpress

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