Pub Date : 2026-02-01DOI: 10.1016/j.tibs.2025.07.004
Sidak Minocha , Marta Oliva-Santiago , Sampath Amitash Gadi , Julien P. Duxin
Lesions on DNA threaten the integrity of replicating genomes, necessitating DNA damage tolerance mechanisms to bypass these lesions and ensure complete duplication of the genome. Lesion bypass by DNA polymerases can occur through either translesion DNA synthesis, which directly synthesizes across the damage, or template switching, which uses the undamaged sister strand as a template to circumvent the lesion. These processes are facilitated by replication fork reversal and/or replication repriming mechanisms, which modulate the progression of the replication fork and its positioning relative to the lesion. Despite the fundamental concepts of lesion bypass being accepted for decades, many aspects remain unresolved. This review revisits these concepts in light of recent advances and highlights the key questions persisting in the field.
DNA损伤威胁到复制基因组的完整性，需要DNA损伤耐受机制来绕过这些损伤，确保基因组的完整复制。DNA聚合酶绕过病变可以通过翻译DNA合成（transesion DNA synthesis）或模板切换（template switching）发生，前者直接在损伤处合成，后者使用未损伤的姊妹链作为模板绕过病变。复制叉逆转和/或复制重发机制促进了这些过程，这些机制调节了复制叉的进展及其相对于病变的定位。尽管病变绕道的基本概念已被接受了几十年，但许多方面仍未解决。这篇综述根据最近的进展重新审视了这些概念，并强调了该领域持续存在的关键问题。
{"title":"Just bypass it: mechanisms of DNA damage tolerance","authors":"Sidak Minocha , Marta Oliva-Santiago , Sampath Amitash Gadi , Julien P. Duxin","doi":"10.1016/j.tibs.2025.07.004","DOIUrl":"10.1016/j.tibs.2025.07.004","url":null,"abstract":"<div><div>Lesions on DNA threaten the integrity of replicating genomes, necessitating DNA damage tolerance mechanisms to bypass these lesions and ensure complete duplication of the genome. Lesion bypass by DNA polymerases can occur through either translesion DNA synthesis, which directly synthesizes across the damage, or template switching, which uses the undamaged sister strand as a template to circumvent the lesion. These processes are facilitated by replication fork reversal and/or replication repriming mechanisms, which modulate the progression of the replication fork and its positioning relative to the lesion. Despite the fundamental concepts of lesion bypass being accepted for decades, many aspects remain unresolved. This review revisits these concepts in light of recent advances and highlights the key questions persisting in the field.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"51 2","pages":"Pages 107-124"},"PeriodicalIF":11.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938104","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 : 2026-02-01DOI: 10.1016/j.tibs.2025.11.003
Mohd Y. Bhat , Xin Liu
Polycomb repressive complex 2 (PRC2) is a key epigenetic enzyme complex that mediates developmental gene repression mainly by depositing the repressive H3K27me3 histone mark. PRC2 operates through its distinct forms, PRC2.1 and PRC2.2, each defined by unique accessory subunits, with additional complexity introduced by other molecular variants such as developmentally regulated homologs and isoforms. PRC2 function is primarily dictated by its enzymatic activity and chromatin recruitment, both of which are rigorously controlled during development and can be dysregulated by disease-associated mutations and oncoproteins. Structural biology has begun to provide important mechanistic insights into various aspects of PRC2 assembly, catalysis, chromatin targeting, and cellular regulation at atomic resolution, addressing several longstanding questions about the Polycomb repression system.
{"title":"Emerging structural insights into PRC2 function in development and disease","authors":"Mohd Y. Bhat , Xin Liu","doi":"10.1016/j.tibs.2025.11.003","DOIUrl":"10.1016/j.tibs.2025.11.003","url":null,"abstract":"<div><div>Polycomb repressive complex 2 (PRC2) is a key epigenetic enzyme complex that mediates developmental gene repression mainly by depositing the repressive H3K27me3 histone mark. PRC2 operates through its distinct forms, PRC2.1 and PRC2.2, each defined by unique accessory subunits, with additional complexity introduced by other molecular variants such as developmentally regulated homologs and isoforms. PRC2 function is primarily dictated by its enzymatic activity and chromatin recruitment, both of which are rigorously controlled during development and can be dysregulated by disease-associated mutations and oncoproteins. Structural biology has begun to provide important mechanistic insights into various aspects of PRC2 assembly, catalysis, chromatin targeting, and cellular regulation at atomic resolution, addressing several longstanding questions about the Polycomb repression system.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"51 2","pages":"Pages 172-186"},"PeriodicalIF":11.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720004","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 : 2026-02-01DOI: 10.1016/j.tibs.2025.12.006
Jesse Rinehart
A new computational approach from Gasparotto et al. leveraged the AlphaFold protein structure and phosphorylation sites in the PhosphoSitePlus database to predict the structural and functional consequences of modifications found in the interior of human proteins.
{"title":"Cryptic phosphorylation sites provide new structural and functional insights into the human phosphoproteome","authors":"Jesse Rinehart","doi":"10.1016/j.tibs.2025.12.006","DOIUrl":"10.1016/j.tibs.2025.12.006","url":null,"abstract":"<div><div>A new computational approach from <span><span>Gasparotto <em>et al.</em></span><svg><path></path></svg></span> leveraged the AlphaFold protein structure and phosphorylation sites in the PhosphoSitePlus database to predict the structural and functional consequences of modifications found in the interior of human proteins.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"51 2","pages":"Pages 98-99"},"PeriodicalIF":11.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146016857","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 : 2026-01-22DOI: 10.1016/j.tibs.2025.12.011
Kathy Darragh
Burkhardt et al. reveal that diterpene synthases diversified early in octocoral evolution, resulting in functionally conserved clades across lineages. Their findings highlight octocorals as an exciting system to study the evolutionary origins and dynamics of terpene synthase enzymes in animals.
{"title":"Ancient enzyme diversification underpins octocoral chemical diversity.","authors":"Kathy Darragh","doi":"10.1016/j.tibs.2025.12.011","DOIUrl":"https://doi.org/10.1016/j.tibs.2025.12.011","url":null,"abstract":"<p><p>Burkhardt et al. reveal that diterpene synthases diversified early in octocoral evolution, resulting in functionally conserved clades across lineages. Their findings highlight octocorals as an exciting system to study the evolutionary origins and dynamics of terpene synthase enzymes in animals.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040173","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 : 2026-01-22DOI: 10.1016/j.tibs.2025.12.013
Xu Liu, Kang Xie, Ge Shan
Mitochondria-encoded circular RNAs (mecciRNAs) are a newly identified class of RNAs present across animal species. Recent advances have improved their identification and characterization. Here, we highlight the current knowledge of mecciRNAs, particularly in mammals, where they have been implicated in multiple physiological and pathological processes.
{"title":"New insights into mitochondria-encoded circular RNAs and their functions.","authors":"Xu Liu, Kang Xie, Ge Shan","doi":"10.1016/j.tibs.2025.12.013","DOIUrl":"https://doi.org/10.1016/j.tibs.2025.12.013","url":null,"abstract":"<p><p>Mitochondria-encoded circular RNAs (mecciRNAs) are a newly identified class of RNAs present across animal species. Recent advances have improved their identification and characterization. Here, we highlight the current knowledge of mecciRNAs, particularly in mammals, where they have been implicated in multiple physiological and pathological processes.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040139","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 : 2026-01-16DOI: 10.1016/j.tibs.2025.12.014
Laura Quintero-Pantoja, Gonzalo Millán-Zambrano
Metabolic enzymes are emerging as key regulators of nuclear processes. A recent study by Srivastava et al. shows that the nucleotide biosynthetic enzyme phosphoribosyl pyrophosphate synthetase 1 participates in early histone maturation, highlighting a direct molecular link between metabolic state and chromatin assembly.
{"title":"A metabolic link between DNA synthesis and chromatin assembly.","authors":"Laura Quintero-Pantoja, Gonzalo Millán-Zambrano","doi":"10.1016/j.tibs.2025.12.014","DOIUrl":"https://doi.org/10.1016/j.tibs.2025.12.014","url":null,"abstract":"<p><p>Metabolic enzymes are emerging as key regulators of nuclear processes. A recent study by Srivastava et al. shows that the nucleotide biosynthetic enzyme phosphoribosyl pyrophosphate synthetase 1 participates in early histone maturation, highlighting a direct molecular link between metabolic state and chromatin assembly.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145994086","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 : 2026-01-14DOI: 10.1016/j.tibs.2025.12.004
Kaitlyn Toy, Jenna N Beyer, George M Burslem
Understanding the highly dynamic nature of many cellular processes requires techniques that provide access to proteins with precise spatial or temporal control. While genetically encodable tags provide experimental access to a protein of interest, these traditional tags lack adequate spatial or temporal resolution and often add significant bulk to a protein of interest. To this end, chemical biology tagging strategies that can covalently tag proteins with small molecules or noncanonical amino acids can incorporate novel functionalities that allow for increased spatial or temporal control. This review summarizes the current strategies for covalent chemical biology tagging in mammalian cells, emphasizing the advantages, limitations, and recent innovations that can potentially expand the cell biologist's repertoire of tools.
{"title":"Chemical biology approaches for protein tagging in mammalian cells.","authors":"Kaitlyn Toy, Jenna N Beyer, George M Burslem","doi":"10.1016/j.tibs.2025.12.004","DOIUrl":"10.1016/j.tibs.2025.12.004","url":null,"abstract":"<p><p>Understanding the highly dynamic nature of many cellular processes requires techniques that provide access to proteins with precise spatial or temporal control. While genetically encodable tags provide experimental access to a protein of interest, these traditional tags lack adequate spatial or temporal resolution and often add significant bulk to a protein of interest. To this end, chemical biology tagging strategies that can covalently tag proteins with small molecules or noncanonical amino acids can incorporate novel functionalities that allow for increased spatial or temporal control. This review summarizes the current strategies for covalent chemical biology tagging in mammalian cells, emphasizing the advantages, limitations, and recent innovations that can potentially expand the cell biologist's repertoire of tools.</p>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":" ","pages":""},"PeriodicalIF":11.0,"publicationDate":"2026-01-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12826794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987448","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Autophagy enables cells to selectively degrade a wide range of macromolecules, and how this process achieves spatial precision within the densely packed cytosol is an active area of investigation. Recent advances suggest that phase separation provides a crucial organizational framework that converts autophagy into a spatiotemporally coordinated and self-organizing process. Biomolecular condensates formed by phase separation can create high-avidity binding platforms between autophagy receptors, scaffold proteins, and the cargo that stabilize transient molecular contacts. The formation of such condensates specifies the cargo and initiates autophagosome formation at defined cellular locations. Simultaneously, physical properties such as wetting govern how condensates interact with membranes, and thus influence engulfment efficiency. Viewing autophagy through the lens of condensate physics not only explains its molecular specificity but also highlights new therapeutic opportunities.
{"title":"Autophagy regulation by phase separation, avidity, and wetting","authors":"Riccardo Babic , Joachim Brenneisen , Florian Wilfling , Claudine Kraft","doi":"10.1016/j.tibs.2025.10.003","DOIUrl":"10.1016/j.tibs.2025.10.003","url":null,"abstract":"<div><div>Autophagy enables cells to selectively degrade a wide range of macromolecules, and how this process achieves spatial precision within the densely packed cytosol is an active area of investigation. Recent advances suggest that phase separation provides a crucial organizational framework that converts autophagy into a spatiotemporally coordinated and self-organizing process. Biomolecular condensates formed by phase separation can create high-avidity binding platforms between autophagy receptors, scaffold proteins, and the cargo that stabilize transient molecular contacts. The formation of such condensates specifies the cargo and initiates autophagosome formation at defined cellular locations. Simultaneously, physical properties such as wetting govern how condensates interact with membranes, and thus influence engulfment efficiency. Viewing autophagy through the lens of condensate physics not only explains its molecular specificity but also highlights new therapeutic opportunities.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"51 1","pages":"Pages 27-38"},"PeriodicalIF":11.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145561980","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 : 2026-01-01DOI: 10.1016/j.tibs.2025.11.008
Taiki Abe , Alice H. Berger
Leucine zipper-like post translational regulator 1 (LZTR1) functions as a RAS degrader, but the molecular basis of LZTR1-RAS regulation has remained unclear. A recent report by Dharmaiah et al. presents crystal structures of the LZTR1 Kelch domain bound to RIT1, MRAS, or KRAS, providing the first atomic-level insights into LZTR1 substrate recognition.
{"title":"New insights in regulation of RAS isoforms revealed by protein structures","authors":"Taiki Abe , Alice H. Berger","doi":"10.1016/j.tibs.2025.11.008","DOIUrl":"10.1016/j.tibs.2025.11.008","url":null,"abstract":"<div><div>Leucine zipper-like post translational regulator 1 (LZTR1) functions as a RAS degrader, but the molecular basis of LZTR1-RAS regulation has remained unclear. A recent report by Dharmaiah <em>et al</em>. presents crystal structures of the LZTR1 Kelch domain bound to RIT1, MRAS, or KRAS, providing the first atomic-level insights into LZTR1 substrate recognition.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"51 1","pages":"Pages 6-7"},"PeriodicalIF":11.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145814624","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 : 2026-01-01DOI: 10.1016/j.tibs.2025.10.006
Konstantinos Kalogeropoulos , Sam P.B. van Beljouw , Dani Feldmann , Daan F. van den Berg , Stan J.J. Brouns
Novel phage defense systems featuring diverse enzymatic activities are continually being discovered. Among these, defense systems employing proteolytic enzymes have been identified, revealing a previously unrecognized enzymatic activity in phage defense. These protease-associated defense systems represent an untapped reservoir for new biotechnological tools and may serve as a springboard for the development of proteome editors. This review outlines recent advancements in the discovery and characterization of protease-containing defense systems, proposes methods for further exploration and investigation of protease activity, and considers the prospect of protease defense systems for modulating protein processing and cell fate.
{"title":"Proteases in bacteriophage defense systems and their potential in bioengineering","authors":"Konstantinos Kalogeropoulos , Sam P.B. van Beljouw , Dani Feldmann , Daan F. van den Berg , Stan J.J. Brouns","doi":"10.1016/j.tibs.2025.10.006","DOIUrl":"10.1016/j.tibs.2025.10.006","url":null,"abstract":"<div><div>Novel phage defense systems featuring diverse enzymatic activities are continually being discovered. Among these, defense systems employing proteolytic enzymes have been identified, revealing a previously unrecognized enzymatic activity in phage defense. These protease-associated defense systems represent an untapped reservoir for new biotechnological tools and may serve as a springboard for the development of proteome editors. This review outlines recent advancements in the discovery and characterization of protease-containing defense systems, proposes methods for further exploration and investigation of protease activity, and considers the prospect of protease defense systems for modulating protein processing and cell fate.</div></div>","PeriodicalId":440,"journal":{"name":"Trends in Biochemical Sciences","volume":"51 1","pages":"Pages 64-79"},"PeriodicalIF":11.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145530373","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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