Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML
| العنوان: | Cohesin mutations alter DNA damage repair and chromatin structure and create therapeutic vulnerabilities in MDS/AML |
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| المؤلفون: | Christina R. Hartigan, John M. Krill-Burger, Jeanne F Rivera, Catherine C. Landers, Sergey V. Venev, Steven A. Carr, Rebecca A. Gorelov, Edwin Chen, Elizabeth A. Morgan, Alan D. D'Andrea, Job Dekker, Mounica Vallurupalli, Edyta Malolepsza, Katerina D. Popova, Amie Holmes, Kasper Lage, Anne-Laure Valton, J. Erika Haydu, Monica Schenone, Melanie Donahue, Sebastian Koochaki, Zuzana Tothova, Benjamin L. Ebert |
| المصدر: | JCI Insight, Vol 6, Iss 3 (2021) JCI Insight |
| بيانات النشر: | American Society for Clinical investigation, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, DNA Repair, Chromosomal Proteins, Non-Histone, Cell Cycle Proteins, Mice, SCID, Mouse models, chemistry.chemical_compound, Mice, 0302 clinical medicine, Mice, Inbred NOD, Tet methylcytosine dioxygenase 2, Nuclear Proteins, General Medicine, U937 Cells, Hematology, Chromatin, Leukemia, Myeloid, Acute, Oncology, 030220 oncology & carcinogenesis, Medicine, Epigenetics, Female, biological phenomena, cell phenomena, and immunity, Research Article, Cohesin complex, DNA damage, Mice, Transgenic, Biology, Poly(ADP-ribose) Polymerase Inhibitors, 03 medical and health sciences, Cell Line, Tumor, Leukemias, Animals, Humans, Replication protein A, Cohesin, Xenograft Model Antitumor Assays, Mice, Mutant Strains, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, Myelodysplastic Syndromes, Mutation, Cancer research, Phthalazines, K562 Cells, DNA, DNA Damage |
| الوصف: | 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. We developed models of cohesin-mutant myelodysplastic syndromes and acute myeloid leukemia and demonstrated a shift from STAG2- to STAG1-cohesin complexes, increased DNA damage, and sensitivity to PARP inhibition. |
| اللغة: | English |
| تدمد: | 2379-3708 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f284522b81d98cbd2e9c78a3b5f31aecTest https://doaj.org/article/04d99d4ec50c41c1a8bc57f790a16758Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f284522b81d98cbd2e9c78a3b5f31aec |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 23793708 |
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