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Telomerase (mis)Regulation by a Cajal Body Trafficking Factor and by Oncogenic Promoter Mutations

日期: 2019-06-12
澳门新浦京学术报告
题目:Telomerase (mis)Regulation by a Cajal Body Trafficking Factor and by Oncogenic Promoter Mutations
主讲人:Chen, Lu, Ph.D.
Postdoctoral Fellow
Department of Biochemistry / Department of Medicine
Division of Hematology
Stanford University
时间:2019年6月27日(星期四)15:00-16:00
地点:吕志和楼B106
摘要
端粒酶RNP,包括非编码RNA和逆转录蛋白亚基,守护着端粒DNA和全基因组的完整性。正常体细胞里在转录水平上沉默的端粒酶,在90%里面的癌细胞里被重新激活。其中非常主要的分子途径是癌症获取端粒酶基因非编码调控区域的点突变 (也是多个癌症基因组最高频率的突变之一)。太少的端粒酶也危及人类健康和长寿,因为人类干细胞的持续功能又仰仗着端粒酶,所以干细胞缺失导致的诸多种儿童早衰疾病中,病人无一不持有端粒酶的突变基因。另外,端粒缺失以致的干细胞和器官衰竭已经被认识是带来人类衰老的重要原因。
陈路的研究涵括端粒酶“生命周期“中的重要分子机理:从其转录调控,RNA转录后修饰和折叠,细胞内定位转运,到端粒的催化延长。在2018年的CELL上,陈路的工作阐述了端粒酶活性调控的新机制:一个普遍认为是Cajal body(核细胞器)的运输蛋白,通过直接调节RNP构象,扮演着端粒酶活性的重要分子开关,为治疗早衰和衰老揭示了新的药物位点。
除了使用经典的生化手段去研究端粒酶的结构和功能,陈路使用xCas9-ABE和piggyBAC transposase 等基因编辑技术,在小鼠里成功敲入了人类癌症中多发的端粒酶基因调控子的单碱基突变。这个全新的小鼠模型会具有更类似人体内的端粒酶的调控模式,可能会成为模拟研究人类癌症生发和抗癌药物筛选的更理想动物模型。

陈路在Joan and Ronald Conaways的指导下在Stowers Institute得到生化和分子生物学博士学位。之后又加入了Steven Artandi在斯坦福大学的实验室,从事博士后工作。期间,先后在Nature, Cell, Molecular Cell, PNAS, JBC等上发表论文。并持有斯坦福大学癌症中心授予的Career Transition Fellowship Award。 陈路毕业于武汉大学,并在中科院生物物理所感染免疫中心唐宏组完成本科论文。

Telomerase RNP, a fascinating noncoding RNA-protein complex that safeguards chromosomal ends, controls the proliferative lifespan of most cells. Telomerase resides only in rare stem/progenitor cells, while is absent in most somas due to transcription silencing of its reverse transcriptase gene TERT. Insufficient telomerase activity limits the ability of stem cells to self-renew, leading to tissue decline in premature aging symptoms and normal aging. Excessive telomerase is selectively acquired by ~90% of cancers, enabling their proliferative immortality. Oncogenic activating mutations in the TERT promoter is the most frequent non-coding mutation in cancer genomes.
To shed light into key steps involved in telomerase biogenesis, I combine genomic editing, enzymology, and unbiased RNA structural probing, and discovered an essential catalytic switch within telomerase RNPs (Chen et al. CELL 2018). The unexpected molecular switch depends on a previously recognized “trafficking factor”, known for tethering noncoding RNAs to lipid-droplet-like Cajal bodies. This finding, together with my other works on telomerase RNA 5’ modification (manuscripts under revision), will provide my independent lab with a list of actionable targets to manipulate telomerase in diseases.
To study telomerase regulation in vivo, I successfully generated a humanized mouse model using CRISPR-Cas9 base editor (xCas9-ABE), in which a single nucleotide change has been knocked into the mouse TERT promoter, mimicking its human counterpart. This novel mouse model is predicted to adopt human-like TERT expression pattern, therefore can potentially serve as an ideal animal model for tissue/stem cell biology and anti-cancer therapeutics.
My PhD studies focused on mRNA transcription and chromatin with Joan and Ronald Conaways in the Stowers Institute for Medical Research. I since joined Steven Artandi’s laboratory in Stanford University as a postdoctoral fellow. I published papers in Nature, Cell, Molecular Cell, PNAS, and JBC, and currently hold a Career Transitioning Fellowship Award granted by Stanford Cancer Institute.

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