Zhu Xiaolan, Wang Xiangyu, Yan Wei, Yang Haibo, Xiang Yufei, Lv Fengping, Shi Yi, Li Hong-Yu, Lan Li
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
NAR Cancer. 2021 Mar 22;3(1):zcab010. doi: 10.1093/narcan/zcab010. eCollection 2021 Mar.
The RNA methyltransferase TRDMT1 has recently emerged as a key regulator of homologous recombination (HR) in the transcribed regions of the genome, but how it is regulated and its relevance in cancer remain unknown. Here, we identified that TRDMT1 is poly-ubiquitinated at K251 by the E3 ligase TRIM28, removing TRDMT1 from DNA damage sites and allowing completion of HR. Interestingly, K251 is adjacent to G155 in the 3D structure, and the G155V mutation leads to hyper ubiquitination of TRDMT1, reduced TRDMT1 levels and impaired HR. Accordingly, a TRDMT1 G155V mutation in an ovarian cancer super responder to platinum treatment. Cells expressing TRDMT1-G155V are sensitive to cisplatin and . In contrast, high expression of TRDMT1 in patients with ovarian cancer correlates with platinum resistance. A potent TRDMT1 inhibitor resensitizes TRDMT1-high tumor cells to cisplatin. These results suggest that TRDMT1 is a promising therapeutic target to sensitize ovarian tumors to platinum therapy.
RNA甲基转移酶TRDMT1最近已成为基因组转录区域中同源重组（HR）的关键调节因子，但其如何被调控以及在癌症中的相关性仍不清楚。在此，我们发现TRDMT1在K251位点被E3连接酶TRIM28多聚泛素化，从而将TRDMT1从DNA损伤位点移除，使HR得以完成。有趣的是，在三维结构中K251与G155相邻，G155V突变导致TRDMT1过度泛素化、TRDMT1水平降低以及HR受损。相应地，在一名对铂类治疗超级敏感的卵巢癌患者中存在TRDMT1 G155V突变。表达TRDMT1 - G155V的细胞对顺铂敏感。相反，卵巢癌患者中TRDMT1的高表达与铂耐药相关。一种有效的TRDMT1抑制剂可使TRDMT1高表达的肿瘤细胞对顺铂重新敏感。这些结果表明，TRDMT1是使卵巢肿瘤对铂类治疗敏感的一个有前景的治疗靶点。
