TTF2 promotes replisome eviction from stalled forks in mitosis DOI Creative Commons
Geylani Can, Maksym Shyian, Archana Krishnamoorthy

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 30, 2024

Abstract When cells enter mitosis with under-replicated DNA, sister chromosome segregation is compromised, which can lead to massive genome instability. The replisome-associated E3 ubiquitin ligase TRAIP mitigates this threat by ubiquitylating the CMG helicase in mitosis, leading disassembly of stalled replisomes, fork cleavage, and restoration structure alternative end-joining. Here, we show that replisome requires phosphorylation mitotic Cyclin B-CDK1 kinase, as well TTF2, a SWI/SNF ATPase previously implicated eviction RNA polymerase from chromosomes. We find TTF2 tethers replisomes using an N-terminal Zinc finger binds phosphorylated adjacent peptide contacts CMG-associated strand DNA ε. This TRAIP-TTF2-pol ε bridge, forms independently domain, essential promote unloading breakage. Conversely, RNAPII chromosomes activity TTF2. conclude undergo CDK- TTF2-dependent structural reorganization underlies cellular response incompletely replicated DNA.

Язык: Английский

Multiple mechanisms for licensing human replication origins DOI
Ran Yang, Olivia Hunker,

Marleigh Wise

и другие.

Nature, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 27, 2024

Язык: Английский

Процитировано

3
Delving into human α1,4-galactosyltransferase acceptor specificity: The role of enzyme dimerization DOI
Krzysztof Mikołajczyk, Karol Wróblewski, Sebastian Kmiecik

и другие.

Biochemical and Biophysical Research Communications, Год журнала: 2024, Номер 736, С. 150486 - 150486

Опубликована: Авг. 3, 2024

Язык: Английский

Процитировано

2
Reading the repertoire: Progress in adaptive immune receptor analysis using machine learning DOI Creative Commons

Timothy J O'Donnell,

Chakravarthi Kanduri, Giulio Isacchini

и другие.

Cell Systems, Год журнала: 2024, Номер 15(12), С. 1168 - 1189

Опубликована: Дек. 1, 2024

Язык: Английский

Процитировано

2
USP37 prevents premature disassembly of stressed replisomes by TRAIP DOI Creative Commons

Olga V. Kochenova,

Giuseppina D’Alessandro, Domenic Pilger

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 4, 2024

The E3 ubiquitin ligase TRAIP associates with the replisome and helps this molecular machine deal replication stress. Thus, promotes DNA inter-strand crosslink repair by triggering disassembly of CDC45-MCM2-7-GINS (CMG) helicases that have converged on these lesions. However, single CMGs stalled temporarily would be deleterious, suggesting must carefully regulated. Here, we demonstrate human cells lacking de-ubiquitylating enzyme USP37 are hypersensitive to topoisomerase poisons other stress-inducing agents. We further show loss rescues hypersensitivity

Язык: Английский

Процитировано

1
FlyRNAi.org 2025 update—expanded resources for new technologies and species DOI Creative Commons
Yanhui Hu, Aram Comjean, Jonathan Rodiger

и другие.

Nucleic Acids Research, Год журнала: 2024, Номер 53(D1), С. D958 - D965

Опубликована: Окт. 22, 2024

The design, analysis and mining of large-scale 'omics studies with the goal advancing biological biomedical understanding require use a range bioinformatics tools, including approaches tailored to needs specific given species and/or technology. FlyRNAi database at Drosophila RNAi Screening Center Transgenic Project (DRSC/TRiP) Functional Genomics Resources (https://fgr.hms.harvard.edu/tools) supports an increasingly broad group technologies species. Recently, for example, we expanded include additional new data-centric resources that facilitate single-cell transcriptomics. In addition, have applied our CRISPR reagent gene-centric in arthropod vectors infectious diseases. Building on previous comprehensive reports database, here focus updated primary tools. Altogether, suite online various stages functional genomics other arthropods, wide analysis, data by biologists experts studying Drosophila, common genetic model species, human biology.

Язык: Английский

Процитировано

1
Molecular Mechanism of PP2A/B55α Inhibition by IER5 DOI Creative Commons

Ruili Cao,

Daniel T.D. Jones, Pan Li

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 29, 2023

PP2A serine/threonine phosphatases are heterotrimeric complexes that execute many essential physiologic functions. These activities modulated by additional regulatory proteins, such as ARPP19, FAM122A, and IER5. Here, we report the cryoelectron microscopy structure of a complex PP2A/B55α with N-terminal structured region IER5 (IER5-N50), which occludes surface on B55α used for substrate recruitment, show IER5-N50 inhibits catalyzed dephosphorylation pTau in biochemical assays. Mutations full-length disrupt its interface interfere co-immunoprecipitation PP2A/B55α. mutations deletions remove nuclear localization sequence suppress cellular events

Язык: Английский

Процитировано

2
Delving into human α1,4-galactosyltransferase acceptor specificity: the role of enzyme dimerization DOI Creative Commons
Krzysztof Mikołajczyk, Karol Wróblewski, Sebastian Kmiecik

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 22, 2024

Abstract Human α1,4-galactosyltransferase (A4galt), a Golgi apparatus-resident GT, synthesizes Gb3 glycosphingolipid (GSL) and P1 glycotope on glycoproteins (GPs), which are receptors for Shiga toxin types 1 2. Despite the significant role of A4galt in glycosylation processes, molecular mechanisms underlying its varied acceptor specificities remain poorly understood. Here, we attempted to elucidate specificity towards GSLs GPs by exploring interaction with GTs various specificities, GP-specific β1,4-galactosyltransferase (B4galt1) GSL-specific isoenzymes 5 6 (B4galt5 B4galt6). Using novel NanoBiT assay, found that can form homodimers heterodimers B4galt1 B4galt5 two cell lines, human embryonic kidney cells (HEK293) Chinese hamster ovary (CHO-Lec2). We A4galt-B4galts preferred N-terminally tagged interactions, while homodimers, favored localization fused tag depended line used. Furthermore, employing AlphaFold state-of-the-art structural prediction, analyzed interactions structures these enzyme complexes. Our analysis highlighted A4galt-B4galt5 heterodimer exhibited highest prediction confidence, indicating heterodimerization determining toward GPs. These findings enhance our knowledge may contribute better comprehension pathomechanisms toxin-related diseases.

Язык: Английский

Процитировано

0
In silicoscreening identifies SHPRH as a novel nucleosome acidic patch interactor DOI Open Access
A James, E. Schmid, Johannes C. Walter

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 27, 2024

Nucleosomes are the fundamental unit of eukaryotic chromatin. Diverse factors interact with nucleosomes to modulate chromatin architecture and facilitate DNA repair, replication, transcription, other cellular processes. An important platform for binding is H2A-H2B acidic patch. Here, we used AlphaFold-Multimer screen over 7000 human proteins nucleosomal patch identify 41 potential binders. We determined cryo-EM structure one hit, SHPRH, nucleosome at 2.8 Å. The confirms predicted interaction, reveals that SHPRH ATPase engages a different location than SF2-type ATPases, clarifies roles SHPRH's domains in recognition. Our results illustrate use

Язык: Английский

Процитировано

0
Prediction and discovery of protein-protein direct interactions and stable complexes based on gene co-expression and co-evolution DOI Creative Commons
Pasquale Miglionico,

Lorenzo Amir Nemati Fard,

Christian Johannes Gloeckner

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 6, 2024

Abstract In this study we employed a data-driven approach to explore the evolutionary and genetic determinants of protein direct interactions stable complex formation in human proteome. We found that simple co-evolutionary co-expression metrics are highly informative complexes. used information train supervised binary classifiers predict either directly involved (as annotated IntAct) or forming complexes (from Complex Portal). former task, our model was able discriminate with an AUROC=0.813, while latter it discriminated interaction AUROC=0.964. both cases, outperformed String, as baseline. Feature importance analysis revealed different contributions prediction these distinct types. Co-evolutionary features, particular those referred domains interfaces, more important interactions. On other hand, features contributed From pairwise predictions generated proteome-wide network clustered assess recovery known from Portal within communities. were recover at higher accuracy compared approaches. conclusion, propose new method well This can be stratify molecular networks, perform discovery functional scale.

Язык: Английский

Процитировано

0
CHK1-mediated regulation of TOP1 catalytic activity suppresses replication and transcription-associated genomic instability DOI Open Access
Ananda Guha Majumdar, Nitish Chauhan,

Pooja Gupta

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Окт. 25, 2024

Abstract The Topoisomerase 1 (TOP1) catalytic cycle involves a TOP1-DNA-covalent-complex (TOP1cc), which, if stabilized, can induce rapid accumulation of potentially lethal DNA double strand breaks (DSBs). Although TOP1cc are critically associated with genome instability, it is not yet precisely known how cells regulate level, under unperturbed physiological-condition, to prevent its and consequences. We discovered key role CHK1 in phosphorylating TOP1 at Serine-320 stimulating TOP1-catalytic minimise wide cancers. Pharmacological or genetic ablation CHK1-mediated TOP1-phosphorylation leads stalled replication forks generates copious amounts replication/transcription-associated DSBs, R-loops transcription-replication collisions, eventually leading chromosomal instability. Further, TOP1ccs stabilized due inhibition efficiently targeted by cellular TOP1cc-removal machineries. Since multiple patient clinical trials ongoing TOP1- CHK1-targeting drugs, current finding regulation may help better understanding the therapeutic outcomes.

Язык: Английский

Процитировано

0