Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response
Abstract The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Star...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Formato: | Artigo |
| Idioma: | English |
| Publicado: |
Springer Nature
2023-07-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Acceso en liña: | https://doi.org/10.15252/emmm.202216431 |
| _version_ | 1826983447746314240 |
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| author | Le Zhang Matthias Wirth Upayan Patra Jacob Stroh Konstandina Isaakidis Leonie Rieger Susanne Kossatz Maja Milanovic Chuanbing Zang Uta Demel Jan Keiten‐Schmitz Kristina Wagner Katja Steiger Roland Rad Florian Bassermann Stefan Müller Ulrich Keller Markus Schick |
| author_facet | Le Zhang Matthias Wirth Upayan Patra Jacob Stroh Konstandina Isaakidis Leonie Rieger Susanne Kossatz Maja Milanovic Chuanbing Zang Uta Demel Jan Keiten‐Schmitz Kristina Wagner Katja Steiger Roland Rad Florian Bassermann Stefan Müller Ulrich Keller Markus Schick |
| author_sort | Le Zhang |
| collection | DOAJ |
| description | Abstract The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5‐SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B‐cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2‐deficiency leads to loss of DDR factors including Claspin (CLSPN) and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post‐translational SUMOylation pathway as a safeguard. The resulting co‐dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co‐targeting of the DDR and SUMOylation as a promising strategy for treating aggressive lymphoma. |
| first_indexed | 2024-03-07T16:40:29Z |
| format | Article |
| id | doaj.art-836a10a55ed242399020398764bfdb7f |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T06:37:10Z |
| publishDate | 2023-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-836a10a55ed242399020398764bfdb7f2024-11-10T12:37:49ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-07-0115911910.15252/emmm.202216431Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage responseLe Zhang0Matthias Wirth1Upayan Patra2Jacob Stroh3Konstandina Isaakidis4Leonie Rieger5Susanne Kossatz6Maja Milanovic7Chuanbing Zang8Uta Demel9Jan Keiten‐Schmitz10Kristina Wagner11Katja Steiger12Roland Rad13Florian Bassermann14Stefan Müller15Ulrich Keller16Markus Schick17Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinDepartment of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinInstitute of Biochemistry II, Goethe University Frankfurt, Medical SchoolGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinDepartment of Medicine III, Klinikum rechts der Isar, Technical University of MunichGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinDepartment of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinDepartment of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinGerman Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)Department of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinDepartment of Hematology, Oncology and Cancer Immunology, Campus Benjamin Franklin, Charité ‐ Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu BerlinAbstract The DNA damage response (DDR) acts as a barrier to malignant transformation and is often impaired during tumorigenesis. Exploiting the impaired DDR can be a promising therapeutic strategy; however, the mechanisms of inactivation and corresponding biomarkers are incompletely understood. Starting from an unbiased screening approach, we identified the SMC5‐SMC6 Complex Localization Factor 2 (SLF2) as a regulator of the DDR and biomarker for a B‐cell lymphoma (BCL) patient subgroup with an adverse prognosis. SLF2‐deficiency leads to loss of DDR factors including Claspin (CLSPN) and consequently impairs CHK1 activation. In line with this mechanism, genetic deletion of Slf2 drives lymphomagenesis in vivo. Tumor cells lacking SLF2 are characterized by a high level of DNA damage, which leads to alterations of the post‐translational SUMOylation pathway as a safeguard. The resulting co‐dependency confers synthetic lethality to a clinically applicable SUMOylation inhibitor (SUMOi), and inhibitors of the DDR pathway act highly synergistic with SUMOi. Together, our results identify SLF2 as a DDR regulator and reveal co‐targeting of the DDR and SUMOylation as a promising strategy for treating aggressive lymphoma.https://doi.org/10.15252/emmm.202216431CHK1DNA damage responselymphomaSLF2SUMO |
| spellingShingle | Le Zhang Matthias Wirth Upayan Patra Jacob Stroh Konstandina Isaakidis Leonie Rieger Susanne Kossatz Maja Milanovic Chuanbing Zang Uta Demel Jan Keiten‐Schmitz Kristina Wagner Katja Steiger Roland Rad Florian Bassermann Stefan Müller Ulrich Keller Markus Schick Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response EMBO Molecular Medicine CHK1 DNA damage response lymphoma SLF2 SUMO |
| title | Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response |
| title_full | Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response |
| title_fullStr | Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response |
| title_full_unstemmed | Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response |
| title_short | Actionable loss of SLF2 drives B‐cell lymphomagenesis and impairs the DNA damage response |
| title_sort | actionable loss of slf2 drives b cell lymphomagenesis and impairs the dna damage response |
| topic | CHK1 DNA damage response lymphoma SLF2 SUMO |
| url | https://doi.org/10.15252/emmm.202216431 |
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