beat365學術報告
題目：Telomerase (mis)Regulation by a Cajal Body Trafficking Factor and by Oncogenic Promoter Mutations
主講人：Chen, Lu, Ph.D.
Postdoctoral Fellow
Department of Biochemistry / Department of Medicine
Division of Hematology
Stanford University
時間：2019年6月27日（星期四）15:00-16:00
地點：呂志和樓B106
摘要
端粒酶RNP，包括非編碼RNA和逆轉錄蛋白亞基，守護着端粒DNA和全基因組的完整性。正常體細胞裡在轉錄水平上沉默的端粒酶，在90%裡面的癌細胞裡被重新激活。其中非常主要的分子途徑是癌症獲取端粒酶基因非編碼調控區域的點突變 （也是多個癌症基因組最高頻率的突變之一）。太少的端粒酶也危及人類健康和長壽，因為人類幹細胞的持續功能又仰仗着端粒酶，所以幹細胞缺失導緻的諸多種兒童早衰疾病中，病人無一不持有端粒酶的突變基因。另外，端粒缺失以緻的幹細胞和器官衰竭已經被認識是帶來人類衰老的重要原因。
陳路的研究涵括端粒酶“生命周期“中的重要分子機理：從其轉錄調控，RNA轉錄後修飾和折疊，細胞内定位轉運，到端粒的催化延長。在2018年的CELL上，陳路的工作闡述了端粒酶活性調控的新機制：一個普遍認為是Cajal body(核細胞器)的運輸蛋白，通過直接調節RNP構象，扮演着端粒酶活性的重要分子開關，為治療早衰和衰老揭示了新的藥物位點。
除了使用經典的生化手段去研究端粒酶的結構和功能，陳路使用xCas9-ABE和piggyBAC transposase 等基因編輯技術，在小鼠裡成功敲入了人類癌症中多發的端粒酶基因調控子的單堿基突變。這個全新的小鼠模型會具有更類似人體内的端粒酶的調控模式，可能會成為模拟研究人類癌症生發和抗癌藥物篩選的更理想動物模型。

陳路在Joan and Ronald Conaways的指導下在Stowers Institute得到生化和分子生物學博士學位。之後又加入了Steven Artandi在斯坦福大學的實驗室，從事博士後工作。期間，先後在Nature, Cell, Molecular Cell, PNAS, JBC等上發表論文。并持有斯坦福大學癌症中心授予的Career Transition Fellowship Award。 陳路畢業于武漢大學，并在中科院生物物理所感染免疫中心唐宏組完成本科論文。

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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