Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.007
Christian F. Baca, Luciano A. Marraffini
Parasitic elements often spread to hosts through the delivery of their nucleic acids to the recipient. This is particularly true for the primary parasites of bacteria, bacteriophages (phages) and plasmids. Although bacterial immune systems can sense a diverse set of infection signals, such as a protein unique to the invader or the disruption of natural host processes, phage and plasmid nucleic acids represent some of the most common molecules that are recognized as foreign to initiate defense. In this review, we will discuss the various elements of invader nucleic acids that can be distinguished by bacterial host immune systems as “non-self” and how this signal is relayed to activate an immune response.
{"title":"Nucleic acid recognition during prokaryotic immunity","authors":"Christian F. Baca, Luciano A. Marraffini","doi":"10.1016/j.molcel.2024.12.007","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.007","url":null,"abstract":"Parasitic elements often spread to hosts through the delivery of their nucleic acids to the recipient. This is particularly true for the primary parasites of bacteria, bacteriophages (phages) and plasmids. Although bacterial immune systems can sense a diverse set of infection signals, such as a protein unique to the invader or the disruption of natural host processes, phage and plasmid nucleic acids represent some of the most common molecules that are recognized as foreign to initiate defense. In this review, we will discuss the various elements of invader nucleic acids that can be distinguished by bacterial host immune systems as “non-self” and how this signal is relayed to activate an immune response.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"10 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.015
Rashmi Agrata, David Komander
The modification of proteins and other biomolecules with the small protein ubiquitin has enthralled scientists from many disciplines for decades, creating a broad research field. Ubiquitin research is particularly rich in molecular and mechanistic understanding due to a plethora of (poly)ubiquitin structures alone and in complex with ubiquitin machineries. Furthermore, due to its favorable properties, ubiquitin serves as a model system for many biophysical and computational techniques. Here, we review the current knowledge of ubiquitin signals through a ubiquitin-centric, structural biology lens. We amalgamate the information from 240 structures in the Protein Data Bank (PDB), combined with single-molecule, molecular dynamics, and nuclear magnetic resonance (NMR) studies, to provide a comprehensive picture of ubiquitin and polyubiquitin structures and dynamics. We close with a discussion of the latest frontiers in ubiquitin research, namely the modification of ubiquitin by other post-translational modifications (PTMs) and the notion that ubiquitin is attached to biomolecules beyond proteins.
{"title":"Ubiquitin—A structural perspective","authors":"Rashmi Agrata, David Komander","doi":"10.1016/j.molcel.2024.12.015","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.015","url":null,"abstract":"The modification of proteins and other biomolecules with the small protein ubiquitin has enthralled scientists from many disciplines for decades, creating a broad research field. Ubiquitin research is particularly rich in molecular and mechanistic understanding due to a plethora of (poly)ubiquitin structures alone and in complex with ubiquitin machineries. Furthermore, due to its favorable properties, ubiquitin serves as a model system for many biophysical and computational techniques. Here, we review the current knowledge of ubiquitin signals through a ubiquitin-centric, structural biology lens. We amalgamate the information from 240 structures in the Protein Data Bank (PDB), combined with single-molecule, molecular dynamics, and nuclear magnetic resonance (NMR) studies, to provide a comprehensive picture of ubiquitin and polyubiquitin structures and dynamics. We close with a discussion of the latest frontiers in ubiquitin research, namely the modification of ubiquitin by other post-translational modifications (PTMs) and the notion that ubiquitin is attached to biomolecules beyond proteins.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"96 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.10.034
Laura López-Hernández, Patrick Toolan-Kerr, Andrew J. Bannister, Gonzalo Millán-Zambrano
Significant effort has been spent attempting to unravel the causal relationship between histone post-translational modifications and fundamental DNA processes, including transcription, replication, and repair. However, less attention has been paid to understanding the reciprocal influence—that is, how DNA processes, in turn, shape the distribution and patterns of histone modifications and how these changes convey information, both temporally and spatially, from one process to another. Here, we review how histone modifications underpin the widespread bidirectional crosstalk between different DNA processes, which allow seemingly distinct phenomena to operate as a unified whole.
人们花费了大量精力试图揭示组蛋白翻译后修饰与 DNA 基本过程（包括转录、复制和修复）之间的因果关系。然而，人们较少关注对相互影响的理解，即 DNA 过程如何反过来影响组蛋白修饰的分布和模式，以及这些变化如何在时间和空间上将信息从一个过程传递到另一个过程。在这里，我们将回顾组蛋白修饰是如何支撑不同DNA过程之间广泛的双向串扰，从而使看似不同的现象作为一个统一的整体运作。
{"title":"Dynamic histone modification patterns coordinating DNA processes","authors":"Laura López-Hernández, Patrick Toolan-Kerr, Andrew J. Bannister, Gonzalo Millán-Zambrano","doi":"10.1016/j.molcel.2024.10.034","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.034","url":null,"abstract":"Significant effort has been spent attempting to unravel the causal relationship between histone post-translational modifications and fundamental DNA processes, including transcription, replication, and repair. However, less attention has been paid to understanding the reciprocal influence—that is, how DNA processes, in turn, shape the distribution and patterns of histone modifications and how these changes convey information, both temporally and spatially, from one process to another. Here, we review how histone modifications underpin the widespread bidirectional crosstalk between different DNA processes, which allow seemingly distinct phenomena to operate as a unified whole.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"41 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.001
Dimitra Tsouraki, A. Marieke Oudelaar
By building synthetic regulatory landscapes, Jensen et al.1 and Thomas et al.2 demonstrate in this issue of Molecular Cell that gene expression levels strongly depend on the genomic distance between enhancers and promoters and that enhancer cooperation can compensate for reduced enhancer activity over large genomic distances.
{"title":"Bridging the gap: How enhancers cooperate to regulate gene expression over large genomic distances","authors":"Dimitra Tsouraki, A. Marieke Oudelaar","doi":"10.1016/j.molcel.2024.12.001","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.001","url":null,"abstract":"By building synthetic regulatory landscapes, Jensen et al.<span><span><sup>1</sup></span></span> and Thomas et al.<span><span><sup>2</sup></span></span> demonstrate in this issue of <em>Molecular Cell</em> that gene expression levels strongly depend on the genomic distance between enhancers and promoters and that enhancer cooperation can compensate for reduced enhancer activity over large genomic distances.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"17 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.014
Gregor Diensthuber, Eva Maria Novoa
RNA modifications are conserved chemical features found in all domains of life and across diverse RNA biotypes, shaping gene expression profiles and enabling rapid responses to environmental changes. Their broad chemical diversity and dynamic nature pose significant challenges for studying them comprehensively. These limitations can now be addressed through direct RNA nanopore sequencing (DRS), which allows simultaneous identification of diverse RNA modification types at single-molecule and single-nucleotide resolution. Here, we review recent efforts pioneering the use of DRS to better understand the epitranscriptomic landscape. We highlight how DRS can be applied to investigate different RNA biotypes, emphasizing the use of specialized library preparation protocols and downstream bioinformatic workflows to detect both natural and synthetic RNA modifications. Finally, we provide a perspective on the future role of DRS in epitranscriptomic research, highlighting remaining challenges and emerging opportunities from improved sequencing yields and accuracy enabled by the latest DRS chemistry.
{"title":"Charting the epitranscriptomic landscape across RNA biotypes using native RNA nanopore sequencing","authors":"Gregor Diensthuber, Eva Maria Novoa","doi":"10.1016/j.molcel.2024.12.014","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.014","url":null,"abstract":"RNA modifications are conserved chemical features found in all domains of life and across diverse RNA biotypes, shaping gene expression profiles and enabling rapid responses to environmental changes. Their broad chemical diversity and dynamic nature pose significant challenges for studying them comprehensively. These limitations can now be addressed through direct RNA nanopore sequencing (DRS), which allows simultaneous identification of diverse RNA modification types at single-molecule and single-nucleotide resolution. Here, we review recent efforts pioneering the use of DRS to better understand the epitranscriptomic landscape. We highlight how DRS can be applied to investigate different RNA biotypes, emphasizing the use of specialized library preparation protocols and downstream bioinformatic workflows to detect both natural and synthetic RNA modifications. Finally, we provide a perspective on the future role of DRS in epitranscriptomic research, highlighting remaining challenges and emerging opportunities from improved sequencing yields and accuracy enabled by the latest DRS chemistry.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"4 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986974","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In recent years, computational methods and artificial intelligence approaches have proven uniquely suited for studying patterns in molecular biology. In this focus issue, we spoke with researchers about using these tools to address various biological questions and explore both current implications and future possibilities.
{"title":"Artificial intelligence in molecular biology","authors":"Anshul Kundaje, Katherine S. Pollard, Jian Ma, Xing Chang, Mengjie Chen, Remo Rohs","doi":"10.1016/j.molcel.2024.12.013","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.013","url":null,"abstract":"In recent years, computational methods and artificial intelligence approaches have proven uniquely suited for studying patterns in molecular biology. <span><span>In this focus issue</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, we spoke with researchers about using these tools to address various biological questions and explore both current implications and future possibilities<strong>.</strong>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"54 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.020
Demis Menolfi
Section snippets
Main text
Patterns can be broadly defined as regular repetitions in contrast to random or casual arrangements. They are associated with order and are often governed by underlying rules. Close inspection of the natural world reveals pervasive patterns that are more common than one might think. For example, macroscopic patterns in the animal and plant kingdoms appear in the stripes of a zebra or the spiral arrangement of a pinecone’s scales. In the microscopic world, the internal organization of cells
{"title":"Exploring patterns in molecular biology","authors":"Demis Menolfi","doi":"10.1016/j.molcel.2024.12.020","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.020","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>Patterns can be broadly defined as regular repetitions in contrast to random or casual arrangements. They are associated with order and are often governed by underlying rules. Close inspection of the natural world reveals pervasive patterns that are more common than one might think. For example, macroscopic patterns in the animal and plant kingdoms appear in the stripes of a zebra or the spiral arrangement of a pinecone’s scales. In the microscopic world, the internal organization of cells</section></section>","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"37 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.019
Leandro N. Ventimiglia, Aleksej Zelezniak
In a recent study in Nature, Gosai et al.1 introduce a framework to engineer and validate synthetic DNA regulatory elements showing cell-type-specific activity in human cell lines, closing the distance to the machine-driven design of functional regulatory sequences with therapeutic applications in humans.
在最近发表于《自然》（Nature）的一项研究中，Gosai 等人1 提出了一个框架，用于设计和验证在人类细胞系中显示出细胞类型特异性活性的合成 DNA 调控元件，从而拉近了机器驱动的功能性调控序列设计与人类治疗应用之间的距离。
{"title":"Programming of synthetic regulatory DNA for cell-type targeting in humans","authors":"Leandro N. Ventimiglia, Aleksej Zelezniak","doi":"10.1016/j.molcel.2024.12.019","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.019","url":null,"abstract":"In a recent study in <em>Nature</em>, Gosai et al.<span><span><sup>1</sup></span></span> introduce a framework to engineer and validate synthetic DNA regulatory elements showing cell-type-specific activity in human cell lines, closing the distance to the machine-driven design of functional regulatory sequences with therapeutic applications in humans.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"24 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142987000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.10.035
Zhiming Li, Zhiguo Zhang
DNA replication, a fundamental process in all living organisms, proceeds with continuous synthesis of the leading strand by DNA polymerase ε (Pol ε) and discontinuous synthesis of the lagging strand by polymerase δ (Pol δ). This inherent asymmetry at each replication fork necessitates the development of methods to distinguish between these two nascent strands in vivo. Over the past decade, strand-specific sequencing strategies, such as enrichment and sequencing of protein-associated nascent DNA (eSPAN) and Okazaki fragment sequencing (OK-seq), have become essential tools for studying chromatin replication in eukaryotic cells. In this review, we outline the foundational principles underlying these methodologies and summarize key mechanistic insights into DNA replication, parental histone transfer, epigenetic inheritance, and beyond, gained through their applications. Finally, we discuss the limitations and challenges of current techniques, highlighting the need for further technological innovations to better understand the dynamics and regulation of chromatin replication in eukaryotic cells.
{"title":"A tale of two strands: Decoding chromatin replication through strand-specific sequencing","authors":"Zhiming Li, Zhiguo Zhang","doi":"10.1016/j.molcel.2024.10.035","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.10.035","url":null,"abstract":"DNA replication, a fundamental process in all living organisms, proceeds with continuous synthesis of the leading strand by DNA polymerase ε (Pol ε) and discontinuous synthesis of the lagging strand by polymerase δ (Pol δ). This inherent asymmetry at each replication fork necessitates the development of methods to distinguish between these two nascent strands <em>in vivo</em>. Over the past decade, strand-specific sequencing strategies, such as enrichment and sequencing of protein-associated nascent DNA (eSPAN) and Okazaki fragment sequencing (OK-seq), have become essential tools for studying chromatin replication in eukaryotic cells. In this review, we outline the foundational principles underlying these methodologies and summarize key mechanistic insights into DNA replication, parental histone transfer, epigenetic inheritance, and beyond, gained through their applications. Finally, we discuss the limitations and challenges of current techniques, highlighting the need for further technological innovations to better understand the dynamics and regulation of chromatin replication in eukaryotic cells.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"75 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-16DOI: 10.1016/j.molcel.2024.12.012
Varun Sahu, Chao Lu
Cells integrate metabolic information into core molecular processes such as transcription to adapt to environmental changes. Chromatin, the physiological template of the eukaryotic genome, has emerged as a sensor and rheostat for fluctuating intracellular metabolites. In this review, we highlight the growing list of chromatin-associated metabolites that are derived from diverse sources. We discuss recent advances in our understanding of the mechanisms by which metabolic enzyme activities shape the chromatin structure and modifications, how specificity may emerge from their seemingly broad effects, and technologies that facilitate the study of epigenome-metabolome interplay. The recognition that metabolites are immanent components of the chromatin regulatory network has significant implications for the evolution, function, and therapeutic targeting of the epigenome.
{"title":"Metabolism-driven chromatin dynamics: Molecular principles and technological advances","authors":"Varun Sahu, Chao Lu","doi":"10.1016/j.molcel.2024.12.012","DOIUrl":"https://doi.org/10.1016/j.molcel.2024.12.012","url":null,"abstract":"Cells integrate metabolic information into core molecular processes such as transcription to adapt to environmental changes. Chromatin, the physiological template of the eukaryotic genome, has emerged as a sensor and rheostat for fluctuating intracellular metabolites. In this review, we highlight the growing list of chromatin-associated metabolites that are derived from diverse sources. We discuss recent advances in our understanding of the mechanisms by which metabolic enzyme activities shape the chromatin structure and modifications, how specificity may emerge from their seemingly broad effects, and technologies that facilitate the study of epigenome-metabolome interplay. The recognition that metabolites are immanent components of the chromatin regulatory network has significant implications for the evolution, function, and therapeutic targeting of the epigenome.","PeriodicalId":18950,"journal":{"name":"Molecular Cell","volume":"30 1","pages":""},"PeriodicalIF":16.0,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142986976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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