허준영 (Rutgers, The State University of New Jersey) | 한빛사논문 > 한빛사

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조회379

허준영Joonyoung Her

Rutgers, The State University of New Jersey

J. Clin. Invest., Mar 26 2024, 134 (10) e167419 | https://doi.org/10.1172/JCI167419 RNF4 sustains Myc-driven tumorigenesis by facilitating DNA replication

Joonyoung Her,¹ Haiyan Zheng,² and Samuel F. Bunting¹

¹Department of Molecular Biology and Biochemistry and

²Biological Mass Spectrometry Facility, Rutgers, The State University of New Jersey, Piscataway, New Jersey, USA.

Address correspondence to: Samuel F. Bunting

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.

논문정보

형식Research article
게재일2024년 03월 (BRIC 등록일 2024-06-03)
연구진국외 연구진
분야 생명과학 > 세포생물학

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