Helmholtz Gemeinschaft


Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response

PDF (Original Article) - Requires a PDF viewer such as GSview, Xpdf or Adobe Acrobat Reader
[img] Other (Supporting Information)

Item Type:Article
Title:Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response
Creators Name:Zhang, L. and Wirth, M. and Patra, U. and Stroh, J. and Isaakidis, K. and Rieger, L. and Kossatz, S. and Milanovic, M. and Zang, C. and Demel, U. and Keiten-Schmitz, J. and Wagner, K. and Steiger, K. and Rad, R. and Bassermann, F. and Müller, S. and Keller, U. and Schick, M.
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.
Keywords:CHK1, DNA Damage Response, Lymphoma, SLF2, SUMO
Source:EMBO Molecular Medicine
Publisher:EMBO Press / Wiley
Page Range:e16431
Date:September 2023
Official Publication:https://doi.org/10.15252/emmm.202216431
PubMed:View item in PubMed

Repository Staff Only: item control page


Downloads per month over past year

Open Access
MDC Library