Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations.
Effect of Single-Residue Mutations on CTCF Binding to DNA: Insights from Molecular Dynamics Simulations.
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DOI：
10.3390/ijms24076395
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发表时间：
2023-03-29
影响因子：
5.6
通讯作者：
Schlick, Tamar
中科院分区：
文献类型：
--
作者：
Mao, Albert;Chen, Carrie;Portillo-Ledesma, Stephanie;Schlick, Tamar
在人类和其他真核生物中，DNA被浓缩成染色质纤维，并进一步缠绕成染色体。这种组织允许基因组中的调控元件相互作用，并通过称为拓扑相关结构域（TADs）的区域促进基因表达，这些元件通常在线性DNA中彼此相距遥远。ccctc结合因子（CTCF）是TAD形成的主要组成部分之一，负责招募伴侣蛋白（内聚蛋白）在TAD内进行环挤压并促进适当的基因表达。由于单残基CTCF突变与人类多种癌症的发展有关，我们的目标是更好地了解这些突变如何影响CTCF结构及其与DNA的相互作用。为此，我们比较了野生型CTCF - dna复合物的全原子分子动力学模拟与八种不同的癌症相关CTCF突变序列的模拟。我们发现，与野生型蛋白相比，大多数突变体具有较低的结合能，导致形成不太稳定的复合物。根据突变的类型和位置，这种稳定性的丧失可归因于静电电位的主要变化，CTCF和DNA之间氢键的丧失，和/或特定锌指的不稳定。有趣的是，特定手指的某些突变可以影响与其他手指DNA的相互作用，这就解释了为什么仅仅单个突变就会损害CTCF的功能。总的来说，这些结果为实验观察提供了机制见解，并进一步强调了CTCF在染色质结构和基因表达调控中的重要性。
In humans and other eukaryotes, DNA is condensed into chromatin fibers that are further wound into chromosomes. This organization allows regulatory elements in the genome, often distant from each other in the linear DNA, to interact and facilitate gene expression through regions known as topologically associating domains (TADs). CCCTC–binding factor (CTCF) is one of the major components of TAD formation and is responsible for recruiting a partner protein, cohesin, to perform loop extrusion and facilitate proper gene expression within TADs. Because single-residue CTCF mutations have been linked to the development of a variety of cancers in humans, we aim to better understand how these mutations affect the CTCF structure and its interaction with DNA. To this end, we compare all-atom molecular dynamics simulations of a wildtype CTCF–DNA complex to those of eight different cancer-linked CTCF mutant sequences. We find that most mutants have lower binding energies compared to the wildtype protein, leading to the formation of less stable complexes. Depending on the type and position of the mutation, this loss of stability can be attributed to major changes in the electrostatic potential, loss of hydrogen bonds between the CTCF and DNA, and/or destabilization of specific zinc fingers. Interestingly, certain mutations in specific fingers can affect the interaction with the DNA of other fingers, explaining why mere single mutations can impair CTCF function. Overall, these results shed mechanistic insights into experimental observations and further underscore CTCF’s importance in the regulation of chromatin architecture and gene expression.
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影响因子：
5.5
作者：
Goetz, Andreas W.;Williamson, Mark J.;Xu, Dong;Poole, Duncan;Le Grand, Scott;Walker, Ross C.
通讯作者：
Walker, Ross C.
影响因子：
64.5
作者：
Lupiáñez DG;Kraft K;Heinrich V;Krawitz P;Brancati F;Klopocki E;Horn D;Kayserili H;Opitz JM;Laxova R;Santos-Simarro F;Gilbert-Dussardier B;Wittler L;Borschiwer M;Haas SA;Osterwalder M;Franke M;Timmermann B;Hecht J;Spielmann M;Visel A;Mundlos S
通讯作者：
Mundlos S
影响因子：
48
作者：
Ivani I;Dans PD;Noy A;Pérez A;Faustino I;Hospital A;Walther J;Andrio P;Goñi R;Balaceanu A;Portella G;Battistini F;Gelpí JL;González C;Vendruscolo M;Laughton CA;Harris SA;Case DA;Orozco M
通讯作者：
Orozco M
影响因子：
4.6
作者：
Chan, Ka Lam;Bakman, Inna;Marts, Amy R.;Batir, Yuksel;Dowd, Terry L.;Tierney, David L.;Gibney, Brian R.
通讯作者：
Gibney, Brian R.
DOI：
10.1007/s00018-021-03946-z
发表时间：
2021-12
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
--
作者：
Bailey CG;Gupta S;Metierre C;Amarasekera PMS;O'Young P;Kyaw W;Laletin T;Francis H;Semaan C;Sharifi Tabar M;Singh KP;Mullighan CG;Wolkenhauer O;Schmitz U;Rasko JEJ
通讯作者：
Rasko JEJ