UMMS Affiliation

Program in Systems Biology; Department of Biochemistry and Molecular Pharmacology

Publication Date

2021-02-08

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Cancer Biology | Cell Biology | Hematology | Hemic and Lymphatic Diseases | Neoplasms | Oncology | Structural Biology

Abstract

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2-mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.

Keywords

Epigenetics, Hematology, Leukemias, Mouse models, Oncology

Rights and Permissions

Copyright: © 2021, Tothova et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

DOI of Published Version

10.1172/jci.insight.142149

Source

Tothova Z, Valton AL, Gorelov RA, Vallurupalli M, Krill-Burger JM, Holmes A, Landers CC, Haydu JE, Malolepsza E, Hartigan C, Donahue M, Popova KD, Koochaki S, Venev SV, Rivera J, Chen E, Lage K, Schenone M, D'Andrea AD, Carr SA, Morgan EA, Dekker J, Ebert BL. Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML. JCI Insight. 2021 Feb 8;6(3):142149. doi: 10.1172/jci.insight.142149. PMID: 33351783. Link to article on publisher's site

Journal/Book/Conference Title

JCI insight

Comments

Full author list omitted for brevity. For the full list of authors, see article.

Related Resources

Link to Article in PubMed

PubMed ID

33351783

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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