Cell Biological mechanisms of centromere drive

着丝粒驱动的细胞生物学机制

基本信息

批准号：
10605289
负责人：
Michael Lampson
金额：
$ 42.66万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2027-05-31
项目状态：
未结题

项目摘要

The seemingly straightforward function of the centromere in directing chromosome segregation is difficult to reconcile with multiple complexities of the underlying molecular machinery, particularly rapid evolution of both centromere DNA and proteins and seemingly redundant pathways linking the DNA to spindle microtubules. This project focuses on centromere drive as a key to unlocking centromere complexity. Selfish centromere DNA sequences bias their transmission to the egg in female meiosis, while centromere proteins evolve to suppress fitness costs of drive while maintaining essential centromere functions. Our recent work determined how selfish centromeres interact with spindle microtubules to bias their segregation. We developed mouse model systems exploiting natural variation in mouse centromere DNA, defined tubulin detyrosination as the key post-translational modification creating meiotic spindle asymmetry, showed that microtubule-destabilizing proteins act as drive effectors exploited by selfish centromeres, established an integrated model for both drive and suppression, and sequenced Murinae genomes for molecular evolution analyses to identify rapidly evolving centromere proteins. Our progress represents crucial steps towards understanding the centromere drive conflict but leaves key gaps in our understanding of drive and suppression and centromere protein evolution, which are addressed in this proposal. First, we will determine how selfish centromeres interact with an asymmetric spindle to bias their segregation. Our previous findings suggest a hypothesis that we will test by manipulating microtubule destabilizing activities at centromeres in live cells, using chemical optogenetic approaches that we developed. Second, we will test whether genetically different centromeres differentially recruit centromere proteins, a central but untested component of the centromere drive theory. Using hybrid mouse zygotes with divergent maternal and paternal centromere satellite DNA sequences as a model system, we will determine if rapidly evolving centromere protein interact differentially with different centromere DNA sequences. Third, we will test for reproductive fitness costs associated with functional differences between centromeres, taking advantage of our hybrid mouse model systems in which paired homologous chromosomes in meiosis have divergent centromeres. Fourth, we will test the concept that centromere proteins have evolved to suppress costs due to functional differences between centromeres, which has been the most challenging part of the drive theory to address experimentally. With tractable experimental systems, a mechanistic model for drive and suppression, and molecular evolution analyses of centromere proteins in place, we will address this challenge by testing whether recurrent changes in rapidly evolving centromere proteins have functional implications consistent with our model. Overall, by investigating centromeres in the context of genetic conflict, this project represents a unique contribution to studies of chromosome segregation and inheritance, with broad consequences for reproductive biology and chromosome evolution.

Centromere在指导染色体隔离时看似直接的功能很难与基本分子机械的多个复杂性调和，尤其是两者的快速发展 Centromere DNA和蛋白质以及将DNA连接到纺锤微管的冗余途径。该项目着重于Centromere驱动器，作为解锁Centromere复杂性的关键。自私的中心 DNA序列将其传播偏向女性减数分裂，而Centromere蛋白演变为抑制驱动器的健身成本，同时保持基本的中心粒功能。我们最近的工作确定自私的中心粒如何与纺锤微管相互作用以偏向其隔离。我们开发了鼠标模型系统利用小鼠中心粒DNA的自然变异，定义的小管蛋白驱散为关键翻译后的修饰产生减数分裂纺锤体不对称，表明微管destabilized 蛋白质充当自私的丝粒利用的驱动效应子，建立了两个驱动器的集成模型和抑制作用，并测序的Murinae基因组进行了分子进化分析，以迅速识别不断发展的中心粒蛋白。我们的进步代表了理解中心的关键步骤驱动冲突，但在我们对驱动器和抑制和丝粒蛋白的理解中留下了关键的差距进化，该提议已解决。首先，我们将确定自私的丝粒如何与不对称的纺锤体，以偏向其隔离。我们以前的发现表明，我们将通过使用化学光学遗传学操纵微粒的微管破坏微粒的活性我们开发的方法。其次，我们将测试遗传上不同的共粒差异招募Centromere蛋白，这是Centromere驱动理论的中心但未测试的组成部分。使用混合动力小鼠的Zygotes具有不同母体和父亲的中心卫星DNA序列作为模型系统，我们将确定迅速发展的中心米蛋白是否与不同的中心粒DNA差异相互作用序列。第三，我们将测试与功能差异相关的生殖健身成本 Centromeres，利用我们的混合小鼠模型系统，其中配对的同源染色体在减数分裂中，有不同的中心粒。第四，我们将测试Centromere蛋白已经进化的概念由于centromeres之间的功能差异而抑制成本，这是最具挑战性的驱动理论的一部分，以实验解决。使用可拖动的实验系统，机械模型对于驱动和抑制作用，以及对丝粒蛋白的分子进化分析，我们将解决通过测试快速发展的中心粒蛋白的复发变化是否具有功能性，这一挑战含义与我们的模型一致。总体而言，通过在遗传冲突的背景下调查中心粒，该项目代表了对染色体分离和继承研究的独特贡献，生殖生物学和染色体进化的后果。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Chromosome instability in tumor cells due to defects in Aurora B mediated error correction at kinetochores.

DOI：
10.1080/15384101.2018.1553340
发表时间：
2018
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
0
作者：
Huang H;Lampson M;Efimov A;Yen TJ
通讯作者：
Yen TJ

Parallel pathways for recruiting effector proteins determine centromere drive and suppression.

DOI：
10.1016/j.cell.2021.07.037
发表时间：
2021-09-16
期刊：
Cell
影响因子：
64.5
作者：
Kumon T;Ma J;Akins RB;Stefanik D;Nordgren CE;Kim J;Levine MT;Lampson MA
通讯作者：
Lampson MA

Evolution of eukaryotic centromeres by drive and suppression of selfish genetic elements.

DOI：
10.1016/j.semcdb.2022.03.026
发表时间：
2022-08
期刊：
SEMINARS IN CELL & DEVELOPMENTAL BIOLOGY
影响因子：
7.3
作者：
Kumon, Tomohiro;Lampson, Michael A.
通讯作者：
Lampson, Michael A.

Reversible optogenetic control of protein function and localization.

蛋白质功能和定位的可逆光遗传学控制。

DOI：
10.1016/bs.mie.2019.05.002
发表时间：
2019
期刊：
Methods in enzymology
影响因子：
0
作者：
Wu,DanielZ;Lackner,RachelM;Aonbangkhen,Chanat;Lampson,MichaelA;Chenoweth,DavidM
通讯作者：
Chenoweth,DavidM

FREEDA: An automated computational pipeline guides experimental testing of protein innovation.