TY  - JOUR
AU  - Zhang, Lei
AU  - Wirth, Matthias
AU  - Patra, Upayan
AU  - Stroh, Jacob
AU  - Isaakidis, Konstandina
AU  - Rieger, Leonie
AU  - Kossatz, Susanne
AU  - Milanovic, Maja
AU  - Zang, Chuanbing
AU  - Demel, Uta
AU  - Keiten-Schmitz, Jan
AU  - Wagner, Kristina
AU  - Steiger, Katja
AU  - Rad, Roland
AU  - Bassermann, Florian
AU  - Müller, Stefan
AU  - Keller, Ulrich
AU  - Schick, Markus
TI  - Actionable loss of SLF2 drives B-cell lymphomagenesis and impairs the DNA damage response.
JO  - EMBO molecular medicine
VL  - 15
IS  - 9
SN  - 1757-4676
CY  - Heidelberg
PB  - EMBO Press
M1  - DKFZ-2023-01422
SP  - e16431
PY  - 2023
N1  - 2023 Sep 11;15(9):e16431
AB  - 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.
KW  - CHK1 (Other)
KW  - DNA damage response (Other)
KW  - SLF2 (Other)
KW  - SUMO (Other)
KW  - lymphoma (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37485814
DO  - DOI:10.15252/emmm.202216431
UR  - https://inrepo02.dkfz.de/record/277705
ER  -