Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation DOI Creative Commons
Hongtae Kim, Won Chan Hwang, Kibeom Park

и другие.

Research Square (Research Square), Год журнала: 2023, Номер unknown

Опубликована: Сен. 20, 2023

Abstract DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, precise roles of these variants in pathogenesis MDS have yet be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes R-loop-induced DNA damage responses (DDR) cooperation with m6A-METTL complex (MAC) and YTHDC1 usingDDX41knockout (KO) andDDX41knock-in (KI, R525H, Y259C) cell lines as well primary samples from patients. Compared wild type (WT),DDX41KO KI led increased levels m6A RNA methylated R-loop damage. Interestingly, found that regulates m6A/R-loop interacting MAC components. Further, promoted recruitment R-loops promoting binding between METTL3 YTHDC1, was dysregulated inDDX41-deficient cells. Collectively, demonstrated plays key role physiological control YTHDC1. These findings provide insights into how defects influence suggest potential therapeutic targets for treatment MDS.

Язык: Английский

Crosstalk between m6A modification and alternative splicing during cancer progression DOI Creative Commons

Zhi‐Man Zhu,

Fu‐Chun Huo, Jian Zhang

и другие.

Clinical and Translational Medicine, Год журнала: 2023, Номер 13(10)

Опубликована: Окт. 1, 2023

Background N6-methyladenosine (m6A), the most prevalent internal mRNA modification in eukaryotes, is added by m6A methyltransferases, removed demethylases and recognised m6A-binding proteins. This significantly influences carious facets of RNA metabolism plays a pivotal role cellular physiological processes. Main body Pre-mRNA alternative splicing, process that generates multiple splice isoforms from multi-exon genes, contributes to protein diversity mammals. Moreover, presence crosstalk between with modifications on pre-mRNAs exerting regulatory control, has been established. The modulates splicing patterns recruiting specific RNA-binding proteins (RBPs) regulate or directly influencing interaction RBPs their target RNAs. Conversely, can impact deposition recognition mRNAs. integration expanded scope therapeutic strategies for cancer treatment, while offers novel insights into mechanistic methylation initiation progression. Conclusion review aims highlight biological functions machinery its implications tumourigenesis. Furthermore, we discuss clinical relevance understanding m6A-dependent tumour therapies.

Язык: Английский

Процитировано

46
Impaired binding affinity of YTHDC1 with METTL3/METTL14 results in R-loop accumulation in myelodysplastic neoplasms with DDX41 mutation DOI Creative Commons
Won Chan Hwang, Kibeom Park, Silvia Park

и другие.

Leukemia, Год журнала: 2024, Номер 38(6), С. 1353 - 1364

Опубликована: Март 21, 2024

Abstract DEAD box helicase 41 (DDX41) mutations are the most prevalent predisposition to familial myelodysplastic syndrome (MDS). However, precise roles of these variants in pathogenesis MDS have yet be elucidated. Here, we discovered a novel mechanism by which DDX41 contributes R-loop-induced DNA damage responses (DDR) cooperation with m6A-METTL complex (MAC) and YTHDC1 using knockout (KO) knock-in (KI, R525H, Y259C) cell lines as well primary samples from patients. Compared wild type (WT), KO KI led increased levels m6A RNA methylated R-loop. Interestingly, found that regulates m6A/R-loop interacting MAC components. Further, promoted recruitment R-loops promoting binding between METTL3 YTHDC1, was dysregulated -deficient cells, contributing genomic instability. Collectively, demonstrated plays key role physiological control YTHDC1. These findings provide insights into how defects influence suggest potential therapeutic targets for treatment MDS.

Язык: Английский

Процитировано

16
Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control? DOI Creative Commons
Ana Janic, Etna Abad, Ivano Amelio

и другие.

Cell Death and Differentiation, Год журнала: 2024, Номер unknown

Опубликована: Фев. 20, 2024

Abstract Genomic instability, a hallmark of cancer, is direct consequence the inactivation tumor suppressor protein p53. Genetically modified mouse models and human samples have revealed that p53 loss results in extensive chromosomal abnormalities, from copy number alterations to structural rearrangements. In this perspective article we explore multifaceted relationship between p53, genomic stability, epigenetic control, highlighting its significance cancer biology. emerges as critical regulator DNA repair mechanisms, influencing key components pathways directly participating processes. role integrity however extends beyond canonical functions. influences also landscape, where it modulates methylation histone modifications. This control impacts expression genes involved suppression oncogenesis. Notably, ability ensure cellular response demethylation contributes maintenance stability by preventing unscheduled transcription repetitive non-coding regions. latter indicates causative p53-mediated suppression. Understanding these mechanisms offers promising avenues for innovative therapeutic strategies targeting dysregulation emphasizes need further research unravel complexities relationship. Ultimately, insights hold potential transform treatment prevention strategies.

Язык: Английский

Процитировано

11
Neoantigens in cancer immunotherapy: focusing on alternative splicing DOI Creative Commons
Peng Huang,

Feng Wen,

Nuerye Tuerhong

и другие.

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июль 11, 2024

Alternative splicing (AS) functions as a crucial program in transcriptional modulation, leading to proteomic diversity and functional alterations of proteins. These actions induce various neoantigens that hold prognostic significance contribute aspects cancer progression, including immune responses against cancer. The advent immunotherapy has remarkably revolutionized tumor therapy. In this regard, AS-derived are potent targets for vaccines chimeric antigen receptor (CAR) T cell therapies. review, we outline serve promising immunotherapeutic guide strategies. This evidence contributes deeper comprehension the complexity provides novel perspectives techniques precision medicine immunotherapy. Moreover, underscore obstacles awaited be addressed approach become clinically applicable.

Язык: Английский

Процитировано

11
The phosphatase inhibitor LB-100 creates neoantigens in colon cancer cells through perturbation of mRNA splicing DOI Creative Commons
Matheus Henrique Dias, Vladyslava Liudkovska, Jasmine Montenegro Navarro

и другие.

EMBO Reports, Год журнала: 2024, Номер 25(5), С. 2220 - 2238

Опубликована: Апрель 10, 2024

Perturbation of protein phosphorylation represents an attractive approach to cancer treatment. Besides kinase inhibitors, phosphatase inhibitors have been shown anti-cancer activity. A prime example is the small molecule LB-100, inhibitor phosphatases 2A/5 (PP2A/PP5), enzymes that affect cellular physiology. LB-100 has proven effective in pre-clinical models combination with immunotherapy, but molecular underpinnings this synergy remain understood poorly. We report here a sensitivity mRNA splicing machinery changes response colorectal adenocarcinoma. observe enrichment for differentially phosphorylated sites within cancer-critical nodes U2 snRNP, SRSF and hnRNP proteins. Altered endows LB-100-treated adenocarcinoma cells differential patterns. In PP2A-inhibited cells, over 1000 events exon skipping intron retention regulators genomic integrity. Finally, we show LB-100-evoked alternative leads neoantigens are presented by MHC class 1 at cell surface. Our findings provide potential explanation clinical observations sensitizes immune checkpoint blockade.

Язык: Английский

Процитировано

7
ALKBH5 enhances lipid metabolism reprogramming by increasing stability of FABP5 to promote pancreatic neuroendocrine neoplasms progression in an m6A-IGF2BP2-dependent manner DOI Creative Commons
Jinhao Chen, Mujie Ye, Jian’an Bai

и другие.

Journal of Translational Medicine, Год журнала: 2023, Номер 21(1)

Опубликована: Окт. 19, 2023

Abstract The process of post-transcriptional regulation has been recognized to be significantly impacted by the presence N 6-methyladenosine (m6A) modification. As an m6A demethylase, ALKBH5 shown contribute progression different cancers increasing expression several oncogenes. Hence, a better understanding key targets in cancer cells could potentially lead development new therapeutic targets. However, specific role pancreatic neuroendocrine neoplasms (pNENs) remains largely unknown. Here, we demonstrated that was up-regulated pNENs and played critical tumor growth lipid metabolism. Mechanistically, over-expression found increase FABP5 m6A- IGF2BP2 dependent manner, leading disorders Additionally, activate PI3K/Akt/mTOR signaling pathway, resulting enhanced metabolism proliferation abilities. In conclusion, our study uncovers ALKBH5/IGF2BP2/FABP5/mTOR axis as mechanism for aberrant modification highlights molecular basis strategies treatment. Graphical

Язык: Английский

Процитировано

15
Direct RNA sequencing (RNA004) allows for improved transcriptome assessment and near real-time tracking of methylation for medical applications DOI Creative Commons
Charlotte Hewel, Anna Wierczeiko,

Johannes Miedema

и другие.

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

Опубликована: Июль 25, 2024

Abstract Direct RNA sequencing (DRS) is a nanopore-based technique for analyzing in its native form, promising breakthroughs diagnostics and biomarker development. Coupled to RNA002 chemistry, clinical implementation has been challenging due low throughput, accuracy, lack of large-scale RNA-modification models. In this study, we evaluate the improvements achieved by pairing latest RNA004 chemistry with novel modified-base-calling models pseudouridine N 6 -methyladenosine using diverse samples from cell lines, synthetic oligos, human blood. Finally, present first application DRS confirming loss methylation patient carrying truncating mutations methyltransferase METTL5 . Conclusively, combined use base-calling significantly improved site-specific detection modifications. From perspective, offer an outlook on potential suitability routine quality assessments therapeutics.

Язык: Английский

Процитировано

6
Epitranscriptome in action: RNA modifications in the DNA damage response DOI Creative Commons
Blerta Xhemalçe, Kyle M. Miller, Natalia Gromak

и другие.

Molecular Cell, Год журнала: 2024, Номер 84(19), С. 3610 - 3626

Опубликована: Окт. 1, 2024

Язык: Английский

Процитировано

6
Infectious bursal disease virus affecting interferon regulatory factor 7 signaling through VP3 protein to facilitate viral replication DOI Creative Commons
Zhiyuan Wang, Chen Yang, Yanyan Chen

и другие.

Frontiers in Cellular and Infection Microbiology, Год журнала: 2025, Номер 14

Опубликована: Янв. 13, 2025

Interferon regulatory factor 7 (IRF7)-mediated type I interferon antiviral response is crucial for regulating the host following viral infection in chickens. Infectious bursal disease virus (IBDV) a double-stranded RNA that induces immune suppression and high mortality rates chickens aged 3-6 weeks. Previous studies have shown IBDV antagonizes production to facilitate replication cell, IRF7 signaling might play an important role. However, underlying mechanisms enable block pathway remain unclear. In this study, we found IFN-β expression were suppressed DF-1 cells during with very virulent (vvIBDV), but not attenuated IBDV, while continued replicate. Overexpression of inhibits knocking down promotes replication. couldn't compensate protein level vvIBDV-infected cells, which suggested was degraded by infection. By using inhibitors, degradation be related proteasome pathway. Further study revealed observed interact colocalize VP3 protein. Consistent results, inhibit IRF7-IFN-β expression, affect via All these results suggest exploits affecting its cells. These findings novel mechanism uses evade defense.

Язык: Английский

Процитировано

0
M6A Demethylase ALKBH5 in Human Diseases: From Structure to Mechanisms DOI Creative Commons

Miaochun Fang,

Liwen Ye,

Yue Zhu

и другие.

Biomolecules, Год журнала: 2025, Номер 15(2), С. 157 - 157

Опубликована: Янв. 21, 2025

N6-methyladenosine (m6A) is the most abundant, dynamically reversible, and evolutionarily conserved internal chemical modification in eukaryotic RNA. It emerging as critical for regulating gene expression at post-transcriptional level by affecting RNA metabolism through, example, pre-mRNA processing, mRNA decay, translation. ALKBH5 has recently been identified an endogenous m6A demethylase implicated a multitude of biological processes. This review provides overview structural functional characteristics involvement diverse human diseases, including metabolic, immune, reproductive, nervous system disorders, well development inhibitors. In summation, this highlights current understanding structure, functions, detailed mechanisms various physiological pathological processes valuable insights clinical applications foundational research within related fields.

Язык: Английский

Процитировано

0