学术演讲：2023年世界顶尖科学家协会奖“生命科学或医学奖”获奖者讲堂

发布日期 2023年11月23日

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在刚刚于上海结束的第六届世界顶尖科学家论坛期间，2023年世界顶尖科学家协会奖“生命科学或医学奖”的三位获奖者相继发表了学术演讲。世界顶尖科学家协会奖获奖者讲堂是顶科协奖年度系列活动的一部分。

主持人：兰迪·谢克曼，2023年世界顶尖科学家协会奖“生命科学或医学奖”遴选委员会主席，2013年诺贝尔生理学或医学奖得主

演讲嘉宾：2023年世界顶尖科学家协会奖“生命科学或医学奖”获奖者

丹妮拉·罗兹（Daniela Rhodes）
英国剑桥MRC分子生物学实验室名誉课题组负责人
演讲标题：The Beginnings of Unravelling the 3D Structure of the Nucleosome
演讲梗概：
By the 1970s, after it had been established that DNA is the genetic material of all living things, the question turned to how the metre-long DNA in each of our cells is compacted into the tiny space inside cells - millions of times smaller than a grain of rice. This led to the discovery and characterization of the composition of the conserved building block of eukaryotic chromosomes, the nucleosome, by Roger Kornberg Jean Thomas and others. In this structure about 146 base pairs of DNA wrap around an octameric complex of histones to form the nucleosome core particle (NCP). In order to understand the precise architecture and function of the nucleosome it became evident that knowledge of its 3D-structure was required. The structural method available half a century ago to determine the atomic structure of proteins was X-ray crystallography, and for this you need crystals. I will describe how the first crystals were obtained in 1976 from NCPs prepared from native sources and hence containing mixed sequence DNA and how this led to a 7Å resolution structure in 1984. Early on it also became evident that more homogeneous NCP preparations would be required to obtain better diffracting crystals and this was achieved by reconstituting NCP with DNA of homogeneous sequence and length. The 3D structure opened up questions of how DNA sequence affect nucleosome positioning and how the nucleosome is remodelled to enable access of the DNA double helix during transcription. Finally, I will jump forward to more recent studies and describe how Cryogenic Electron Microscopy has permitted the rapid determination of the near atomic structure of telomeric chromatin that protects the tips of chromosomes.

蒂莫西·J·里士满（Timothy J. Richmond）
瑞士苏黎世联邦理工学院生物大分子晶体学名誉教授
演讲标题：The Atomic Structure of the Nucleosome Core Particle
演讲梗概：
The DNA of all higher organisms is packaged in chromatin. Chromatin is responsible for 100,000-fold compaction of genomic DNA, yet permits access to factors that regulate and carryout DNA replication, transcription and repair. The nucleosome is the fundamental repeating unit of chromatin and comprises nine histone proteins and 157-240 base pairs of DNA. There are 10’s of millions of nucleosomes in the nucleus of a single cell. The nucleosome core particle prepared from chromatin is the larger part of the nucleosome, lacking only the linker DNA and linker histone protein. The atomic structure of the nucleosome core particle was determined by protein X-ray crystallography. The challenges and achievements that secured the structure, initially at 7 Å, then at 2.8 Å and 1.9 Å resolution will be presented. The structure reveals in atomic detail how the histone proteins are organized and how they bind DNA. The DNA, wrapped in a superhelix around a histone octamer, displays sequence-dependent, smooth and kinked bending. As a consequence of bending, the DNA bound in the nucleosome core differs substantially from Watson-Crick DNA. These and further features that have important implications for nucleosome-nucleosome and nucleosome-factor interactions will be described.

卡洛琳·卢格（Karolin Luger）
美国科罗拉多大学博尔德分校教授、生物化学讲席教授
演讲标题：Genomes Packaged to Perfection, in All Domains of Life
演讲梗概：
The entire blueprint for each cell in the human body is encoded on DNA, an incredibly long and impossibly thin molecule. The basic organizing principle of DNA is the nucleosome, where small segments of DNA are tightly wrapped into nucleoprotein complexes. This profoundly affects access to the information stored on the DNA, and thus determines every cell’s identity and function. This organization also impacts the faithful duplication of the entire genome during cell division, and the cell’s endless and vital efforts to repair potentially fatal and disease-causing breaks and tangles. The three-dimensional (‘atomic’) structure of the nucleosome provided much-needed insight into how this ‘mission impossible’ might be accomplished, and as such has had a profound impact on the fields of genetics and epigenetics.
Over the past 25 years, my lab has continued to study the molecular details of DNA organization in humans. We have applied the techniques of modern structural biology to elucidate the structure and mechanics of the elaborate and complicated machinery that ‘makes and breaks’ nucleosomes. We study how the delicate balance between access and protection of the genome is maintained, and how epigenetic modifications affect nucleosome structure. We also explore the evolutionary origins of the nucleosome, which was a very early and essential acquisition in the emergence of all eukaryotic and multi-cellular life as we know it. Surprisingly, histones do exist in all domains of life, and we investigate histone-based genome packaging in ancient ‘archaebacteria’, in bacteria, and in giant viruses. I will discuss unexpected similarities and differences in how histones are used in these ancient domains of life that likely have combined to form the first eukaryotic cell.