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RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication
Joonyoung Her, … , Haiyan Zheng, Samuel F. Bunting
Joonyoung Her, … , Haiyan Zheng, Samuel F. Bunting
Published March 26, 2024
Citation Information: J Clin Invest. 2024;134(10):e167419. https://doi.org/10.1172/JCI167419.
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Research Article Genetics Oncology

RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication

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Abstract

The mammalian SUMO-targeted E3 ubiquitin ligase Rnf4 has been reported to act as a regulator of DNA repair, but the importance of RNF4 as a tumor suppressor has not been tested. Using a conditional-knockout mouse model, we deleted Rnf4 in the B cell lineage to test the importance of RNF4 for growth of somatic cells. Although Rnf4–conditional-knockout B cells exhibited substantial genomic instability, Rnf4 deletion caused no increase in tumor susceptibility. In contrast, Rnf4 deletion extended the healthy lifespan of mice expressing an oncogenic c-myc transgene. Rnf4 activity is essential for normal DNA replication, and in its absence, there was a failure in ATR-CHK1 signaling of replication stress. Factors that normally mediate replication fork stability, including members of the Fanconi anemia gene family and the helicases PIF1 and RECQL5, showed reduced accumulation at replication forks in the absence of RNF4. RNF4 deficiency also resulted in an accumulation of hyper-SUMOylated proteins in chromatin, including members of the SMC5/6 complex, which contributes to replication failure by a mechanism dependent on RAD51. These findings indicate that RNF4, which shows increased expression in multiple human tumor types, is a potential target for anticancer therapy, especially in tumors expressing c-myc.

Authors

Joonyoung Her, Haiyan Zheng, Samuel F. Bunting

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Figure 5

Genomic instability and cell death in RNF4-deficient cells are dependent on RAD51.

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Genomic instability and cell death in RNF4-deficient cells are dependent...
(A) Western blot analysis of WT and Rnf4Δ/Δ B cells cultured in vitro for 72 hours with mock treatment (–) or with the RAD51 inhibitor RI-1 (5 μM, 10 μM). (B) Analysis of chromosome aberrations in day 2 cultured B cells with or without RI-1 treatment (5 μM, 10 μM). (C) Analysis of CFSE FACS to measure cell proliferation during 72 hours of growth with or without RI-1 treatment (5 μM). (D) As in A, with the RAD51 inhibitor B02 (5 μM, 10 μM). (E) As in B, with B02 (5 μM, 10 μM). (F) As in C, with B02 (5 μM). (G) Viability of B cells, measured by DAPI exclusion, after treatment with RI-1 (5 μM, 10 μM) on day 3. (H) As in G, with B02 (2.5 μM, 5 μM). (I) Measurement of newly replicated DNA by DNA combing after pulsing of cells with CldU and IdU with or without RI-1 or B02 (10 μM in each case). Mean ± SD of n = 3 experiments shown. Error bars in B, C, and E–H represent SD of the mean. P values were calculated by 1-way ANOVA with Dunnett’s multiple-comparison test (B, E, G, and H), unpaired 2-tailed t test (C and F), and 1-way ANOVA with Tukey’s multiple-comparison test (I). P < 0.05 was considered significant. *P < 0.05; **P < 0.01; ***P < 0.001

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