Identification of a point mutation PMLS214L-RAR alpha that alters PML body organization, dynamics and SUMOylation
Identification of a point mutation PMLS214L-RAR alpha that alters PML body organization, dynamics and SUMOylation
复制标题
鉴定改变 PML 身体组织、动力学和 SUMOylation 的点突变 PMLS214L-RAR α
DOI：
10.1016/j.bbrc.2019.02.101
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发表时间：
2019
影响因子：
3.1
通讯作者：
Zhu Hong Hu
中科院分区：
文献类型：
--
作者：
Zhao Shanshan;Shi Peng;Zhong Qihang;Shao Shipeng;Huang Yuxing;Sun Yujie;Wu Congying;Zhu Hong Hu
急性早幼粒细胞白血病（APL）PML-RARα基因突变与三氧化二砷（ATO）或全反式维甲酸（ATRA）耐药相关。我们对APL患者进行了回顾性分析，发现PML-RARα PML部分S214 L突变的患者对ATO和ATRA均耐药。使用超分辨率显微镜检查药物处理后野生型或S214 L突变细胞中PML小体的结构反应。通过单颗粒定量和FRAP分析，确定了不同的蛋白密度和流动性与S214 L突变PML体。我们发现SUMO化和泛素化的改变可能与耐药性有关。综上所述，我们发现PML-RARα上的S214 L突变破坏了PML小体的组织结构和动力学变化，干扰了对ATRA的结构反应和随后的癌蛋白降解。我们的发现为PML小体的结构改变和APL耐药机制提供了新的线索。
Genetic mutations on PML-RARα in acute promyelocytic leukemia (APL) are reported to associate with arsenic trioxide (ATO) or all-trans retinoic acid (ATRA) resistance. Here we performed a retrospective analysis of APL patients and identified that the patient with S214L mutation on the PML moiety of PML-RARα showed resistance to both ATO and ATRA. Super-resolution microcopy was used to examine the structural response of PML bodies in wild-type or the S214L mutant cells upon drug treatment. Different protein density and fluidity were identified with the S214L mutant PML bodies by single particle quantification and FRAP analysis. We discovered that altered SUMOylation and ubiquitination might contribute to the drug resistance. Taken together, we have revealed that the S214L mutation on PML-RARα disrupted the organization of PML body and dynamics changes, perturbing structural responses to ATRA and subsequent oncoprotein degradation. Our findings shed new light on the structural alterations of PML bodies and mechanisms of APL drug resistance.