|
电话：＋86-10-6274 4485 邮箱：zhiqi7@pku.edu.cn 实验室主页：http://cqb.pku.edu.cn/qizhi/ 1999年毕业于北京科技大学获应用物理学学士学位 2002年毕业于北京大学获物理学硕士学位 2006年毕业于美国普渡大学获物理学硕士学位 2013年毕业于美国伊利诺伊大学香槟分校获生物物理计算生物学博士学位 |
担任职务：
北京大学定量生物学中心长聘副教授
研究方向：
单分子生物物理学与非平衡态物理学
研究兴趣：
The ultimate goal of research in my independent laboratory is to develop cutting-edge single-molecule biophysical technologies and establish non-equilibrium physics models to understand the molecular mechanisms underlying functional biomolecular dynamic clusters in molecular biology. Our research focuses on two types of biomolecular dynamic clusters: dsDNA-protein co-condensation and ssDNA-RPA complex. These studies have the potential to lead to the development of new strategies for intervening in human diseases.
1) Deciphering the molecular mechanism of dsDNA-protein co-condensation
Eukaryotic cells utilize lipid membranes to compartmentalize their intracellular organization. However, recent in vivo and in vitro studies have revealed that these cells also employ an alternative strategy for organizing their complex biochemistry. For instance, macromolecules such as nucleic acids and proteins can undergo liquid-liquid phase separation (LLPS) to assemble, resulting in the formation of membrane-free, biomolecular dynamic clusters. The major driving forces for LLPS are protein intrinsically disordered regions (IDRs) and/or multivalent interactions between modular biomacromolecules. These functional clusters play crucial roles in several essential biological functions, while aberrant clusters can lead to various human diseases.
Functional biomolecular dynamic clusters can be formed by individual forms of biomacromolecules or multiple types, identified as single-component condensates or multi-component condensates, respectively. For instance, dsDNA has been found to act as scaffolds for the formation of dsDNA-protein co-condensation. Understanding the molecular mechanism underlying these co-condensations is crucial for deciphering vital cellular processes, such as chromatin formation and transcription initiation condensate formation. Although several studies have focused on dsDNA-protein co-condensation, challenges have arisen in comprehending the underlying principles of co-condensation formation and function. To address this issue, we utilized newly developed single-molecule techniques and non-equilibrium physics to decipher the molecular mechanism of dsDNA-protein co-condensation.
2) Investigating the molecular mechanism of ssDNA-RPA complex
Replication Protein A (RPA) is the major single-stranded DNA (ssDNA)-binding protein in eukaryotes. It acts as the first responder to ssDNA exposure and coordinates downstream DNA metabolic pathways, such as DNA replication and repair. In humans, mutations in RPA have been associated with various diseases, including breast and colon cancer. During DNA replication, RPA participates in initiation, lagging strand synthesis, and replication checkpoint activation. In DNA repair, RPA is crucial for nearly all repair pathways involving ssDNA intermediates, including mismatch repair, nucleotide excision repair (NER), and homologous recombination (HR)-mediated DNA double-strand break (DSB) repair. Although the function of RPA can be modulated by RPA-interacting proteins (RIPs) and post-translational modifications in response to DNA damage, the precise mechanism by which RPA directs the choice of DNA metabolic pathway for the same ssDNA bound remains to be elucidated.
RPA in Saccharomyces cerevisiae is a heterotrimer composed of three subunits: Rfa1, Rfa2, and Rfa3. Each subunit contains at least one oligonucleotide/oligosaccharide-binding fold (OB), also known as the DNA-binding domain (DBD). Rfa1 has four OB folds (DBD-F, DBD-A, DBD-B, and DBD-C), Rfa2 has one OB fold (DBD-D), and Rfa3 has one OB fold (DBD-E). Additionally, Rfa2 has a winged helix-turn-helix (WH) domain at its C-terminus. Currently, it is believed that the WH domain and DBD-F are not involved in ssDNA binding but rather in protein-protein interactions. Despite each DBD having weak affinity with ssDNA (with a dissociation constant in the micromolar range), a cooperative action among the DBDs enables RPA to bind ssDNA tightly, with dissociation constants as low as sub-nanomolar levels. Multiple RPA molecules bind to long ssDNA, forming an ssDNA-RPA complex. This complex has recently been shown to be another type of membrane-free, functional biomolecular dynamic cluster. We utilized newly developed single-molecule techniques and non-equilibrium physics to investigate the molecular mechanism of ssDNA-RPA complex.
工作经历：
2016年1月 - 至今 北京大学定量生物学长聘副教授
2016年1月 - 2023年12月 北京大学定量生物学中心研究员
2013年6月 - 2015年12月 美国哥伦比亚大学医学院博士后
获奖情况：
2023年 北京大学博雅特聘教授
2023年 北京大学优秀共产党员
2022年 国家杰出青年科学基金
2019年 北京大学教学优秀奖
2019年 北京大学优秀共产党员
2018年 北京大学博雅青年学者
2017年 国家海外高层次人才引进计划青年项目
2011年 Lebus graduate scholar award Fellowship (美国伊利诺伊州立大学香槟分校)
学术兼职：
2021年-至今 中国生物物理学会单分子生物学分会副秘书长
2019年-至今 中国生物物理学会生物大分子相分离与相变分会理事
2019年-至今 Faculty Member in the Molecular Biological Physics Section in Faculty Opinions (https://facultyopinions.com)
代表性文章：
At PKU (*co-first author; # corresponding author):
5. Ding, J.*, Li, X.*, Shen, J.*, Zhao, Y., Zhong, S., Lai, L., Niu, H.#, and Qi, Z.# (2023). ssDNA accessibility of Rad51 is regulated by orchestrating multiple RPA dynamics. Nature Communications 14, 3864.
4. Zhou, R., Tian, K., Huang, J., Duan, W., Fu, H., et al., Qi, Z.#, Ji. X.# (2022). CTCF DNA-binding domain undergoes dynamic and selective protein–protein interactions. iScience 25, 105011.
3. Shen, J.*, Zhao, Y.*, Pham, N.T.*, Li, Y., Zhang, Y., Trinidad, J., Ira, G., Qi, Z.#, and Niu, H.# (2022). Deciphering the mechanism of processive ssDNA digestion by the Dna2-RPA ensemble. Nature Communications 13, 359.
2. Zuo, L., Zhang, G., Massett, M., Cheng, J., Guo, Z., Wang, L., Gao, Y., Li, R., Huang, X.#, Li, P.#, Qi, Z.# (2021). Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription. Nature Communications 12, 1491.
The editors at Nature Communications have put together an Editors’ Highlights webpage of recent research called “From molecules and cells to organisms” and our paper was chosen to be featured (www.nature.com/collections/bbcaeejggj).
The editors at Nature Communications have put together an Editors’ Highlights webpage of recent research called “Protein Liquid-Liquid Phase Separation in diseases” and our paper was chosen to be featured (www.nature.com/collections/bbaiabggbh).
1. Zhou, H., Song, Z., Zhong, S., Zuo, L., Qi, Z.#, Qu, L.-J.#, and Lai, L.# (2019). Mechanism of DNA-Induced Phase Separation for Transcriptional Repressor VRN1. Angewandte Chemie (International ed in English) 58, 4858.
Our paper has been selected to be featured in PKU Scientific Research Highlights (2019).
Prior to PKU (+co-second author):
3. Lee, J.Y., Terakawa, T.+, Qi, Z.+, Steinfeld, J.B., Redding, S., Kwon, Y., Gaines, W.A., Zhao, W., Sung, P., and Greene, E.C. (2015). Base triplet stepping by the Rad51/RecA family of recombinases. Science 349, 977-981.
2. Qi, Z., Redding, S., Lee, J.Y., Gibb, B., Kwon, Y., Niu, H.Y., Gaines, W.A., Sung, P., and Greene, E.C. (2015). DNA Sequence Alignment by Microhomology Sampling during Homologous Recombination. Cell 160, 856-869.
1. Qi, Z., Pugh, R.A., Spies, M., and Chemla, Y.R. (2013). Sequence-dependent base pair stepping dynamics in XPD helicase unwinding. Elife 2.
