Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G...Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)progression.Here,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor prognosis.Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen content.Moreover,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs.Thus,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.展开更多
Background:The role of N1-methyladenosine(m1A)in cancer is poorly understood.Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A(TRMT61A)in colorectal cancer(CRC)and its potential as a th...Background:The role of N1-methyladenosine(m1A)in cancer is poorly understood.Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A(TRMT61A)in colorectal cancer(CRC)and its potential as a therapeutic target.Methods:RNA m1A levels were assessed through liquid chromatography-mass spectrometry.The expression and clinical significance of TRMT61Awere investigated across five human CRC cohorts.The function of TRMT61A was elucidated using CRC cell lines,patient-derived organoids,xenografts,and transgenic mouse models.Integrated analyses of m1A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A.A nanoparticle-based small interfering RNA(siRNA)delivery system and a specific inhibitorwere developed to target TRMT61A.The efficacy and safety of targeting TRMT61Awere assessed.Results:Our research revealed a consistent increase in TRMT61A expression and total RNA m1A levels within primary CRCs.High TRMT61A expression was associated with poor prognosis of CRC patients.Through CRISPR/Cas9 screenings,we identified TRMT61A as the most essential gene among m1A regulators.Furthermore,we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m1A-dependent manner.In particular,TRMT61A boosted the mRNA stability of one cut homeobox 2(ONECUT2),which in turn triggered son of sevenless homolog 1(SOS1)transcription,leading to the induction of mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)signaling in CRC.Notably,our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound,pentagalloylglucose.Conclusions:Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m1A-ONECUT2-SOS1-MAPK/ERK pathway.Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.展开更多
Dear Editor,Type 2 diabetes mellitus(T2DM)has been identified as a risk factor for increased severity in acute pancreatitis(AP)(Mikóet al,2018).However,to date,no studies have simultaneously included healthy indi...Dear Editor,Type 2 diabetes mellitus(T2DM)has been identified as a risk factor for increased severity in acute pancreatitis(AP)(Mikóet al,2018).However,to date,no studies have simultaneously included healthy individuals,T2DM patients,and AP patients to investigate which diabetes-associated metabolites are linked to AP severity.展开更多
Dear Editor,Transfer RNA(tRNA)is an indispensable adaptor molecule in the messenger RNA(mRNA)translation machinery,facilitating the conversion of genetic information encoded in mRNA into functional proteins.Numerous p...Dear Editor,Transfer RNA(tRNA)is an indispensable adaptor molecule in the messenger RNA(mRNA)translation machinery,facilitating the conversion of genetic information encoded in mRNA into functional proteins.Numerous posttranscriptional modifications in tRNA have been identified,which play significantroles in modulating tRNA folding,biochemical stability,amino-acylation,and codon–anticodon interaction(Suzuki,2021).TRMT10A,the mammalian homolog of Trm10,incorporates N1-methylguanosine modification at position 9(m^(1)G9)of various cytoplasmic tRNAs,including tRNAGln and tRNAIniMeth(Vilardo et al.,2020).Mutations in human TRMT10A,which is enriched in pancreatic islets and brain(Igoillo-Esteve et al.,2013),are often associated with microcephaly,intellectual disability,early-onset diabetes,and short stature(Igoillo-Esteve et al.,2013;Uçan Tokuçet al.,2024).展开更多
TRMT1 is an N^2-methylguanosine(m^(2)G)and N^2,N^2-methylguanosine((m^(2))_(2)G)methyltransferase that targets G26 of both cytoplasmic and mitochondrial t RNAs.In higher eukaryotes,most cytoplasmic t RNAs with G26 car...TRMT1 is an N^2-methylguanosine(m^(2)G)and N^2,N^2-methylguanosine((m^(2))_(2)G)methyltransferase that targets G26 of both cytoplasmic and mitochondrial t RNAs.In higher eukaryotes,most cytoplasmic t RNAs with G26 carry(m^(2))_(2)G26,although the majority of mitochondrial G26-containing t RNAs carry m^(2)G26 or G26,suggesting differences in the mechanisms by which TRMT1 catalyzes modification of these t RNAs.Loss-of-function mutations of human TRMT1 result in neurological disorders and completely abrogate t RNA:(m^(2))_(2)G26 formation.However,the mechanism underlying the independent catalytic activity of human TRMT1 and identity of its specific substrate remain elusive,hindering a comprehensive understanding of the pathogenesis of neurological disorders caused by TRMT1 mutations.Here,we showed that human TRMT1 independently catalyzes formation of the t RNA:m^(2)G26 or(m^(2))_(2)G26 modification in a substrate-dependent manner,which explains the distinct distribution of m^(2)G26 and(m^(2))_(2)G26 on cytoplasmic and mitochondrial t RNAs.For human TRMT1-mediated t RNA:(m^(2))_(2)G26 formation,the semi-conserved C11:G24 serves as the determinant,and the U10:A25 or G10:C25 base pair is also required,while the size of the variable loop has no effect.We defined the requirements of this recognition mechanism as the“(m^(2))_(2)G26 criteria”.We found that the(m^(2))_(2)G26 modification occurred in almost all the higher eukaryotic t RNAs conforming to these criteria,suggesting the“(m^(2))_(2)G26 criteria”are applicable to other higher eukaryotic t RNAs.展开更多
Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A vari...Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.展开更多
基金This work was supported by the National Key Research and Development Program of China(Nos.2020YFA0113003 and 2018YFC1004803)the Fundamental Research Funds for the Central Universities.
文摘Accumulating evidence has confirmed the links between transfer RNA(tRNA)modifications and tumor progression.The present study is the first to explore the role of tRNA methyltransferase 5(TRMT5),which catalyzes the m1G37 modification of mitochondrial tRNAs in hepatocellular carcinoma(HCC)progression.Here,based on bioinformatics and clinical analyses,we identified that TRMT5 expression was upregulated in HCC,which correlated with poor prognosis.Silencing TRMT5 attenuated HCC proliferation and metastasis both in vivo and in vitro,which may be partially explained by declined extracellular acidification rate(ECAR)and oxygen consumption rate(OCR).Mechanistically,we discovered that knockdown of TRMT5 inactivated the hypoxia-inducible factor-1(HIF-1)signaling pathway by preventing HIF-1αstability through the enhancement of cellular oxygen content.Moreover,our data indicated that inhibition of TRMT5 sensitized HCC to doxorubicin by adjusting HIF-1α.In conclusion,our study revealed that targeting TRMT5 could inhibit HCC progression and increase the susceptibility of tumor cells to chemotherapy drugs.Thus,TRMT5 might be a carcinogenesis candidate gene that could serve as a potential target for HCC therapy.
基金the ethics committee of the Chinese University of Hong Kong(CREC Ref.No.2022.109).
文摘Background:The role of N1-methyladenosine(m1A)in cancer is poorly understood.Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A(TRMT61A)in colorectal cancer(CRC)and its potential as a therapeutic target.Methods:RNA m1A levels were assessed through liquid chromatography-mass spectrometry.The expression and clinical significance of TRMT61Awere investigated across five human CRC cohorts.The function of TRMT61A was elucidated using CRC cell lines,patient-derived organoids,xenografts,and transgenic mouse models.Integrated analyses of m1A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A.A nanoparticle-based small interfering RNA(siRNA)delivery system and a specific inhibitorwere developed to target TRMT61A.The efficacy and safety of targeting TRMT61Awere assessed.Results:Our research revealed a consistent increase in TRMT61A expression and total RNA m1A levels within primary CRCs.High TRMT61A expression was associated with poor prognosis of CRC patients.Through CRISPR/Cas9 screenings,we identified TRMT61A as the most essential gene among m1A regulators.Furthermore,we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m1A-dependent manner.In particular,TRMT61A boosted the mRNA stability of one cut homeobox 2(ONECUT2),which in turn triggered son of sevenless homolog 1(SOS1)transcription,leading to the induction of mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)signaling in CRC.Notably,our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound,pentagalloylglucose.Conclusions:Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m1A-ONECUT2-SOS1-MAPK/ERK pathway.Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.
基金supported by the National Natural Science Foundation of China(82070841 to Yingmei Feng,82200715 to Yuan Dong,32321004 and 92357308 to Guanghou Shui).
文摘Dear Editor,Type 2 diabetes mellitus(T2DM)has been identified as a risk factor for increased severity in acute pancreatitis(AP)(Mikóet al,2018).However,to date,no studies have simultaneously included healthy individuals,T2DM patients,and AP patients to investigate which diabetes-associated metabolites are linked to AP severity.
基金Supplementary material is available at Journal of Molecular Cell Biology online.This study was supported by grants from the National Natural Science Foundation of China(82230075 to D.G.32270159 to J.W.)+2 种基金Guangdong Basic and Applied Basic Research Foundation(2023A1515012613 to J.W.)Shenzhen Science and Technology Program(JCYJ20200109142201695 and KQTD20180411143323605 to D.G.,JCYJ20220530145608018 to J.W.)Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases(ZDSYS20220606100803007 to J.W.).
文摘Dear Editor,Transfer RNA(tRNA)is an indispensable adaptor molecule in the messenger RNA(mRNA)translation machinery,facilitating the conversion of genetic information encoded in mRNA into functional proteins.Numerous posttranscriptional modifications in tRNA have been identified,which play significantroles in modulating tRNA folding,biochemical stability,amino-acylation,and codon–anticodon interaction(Suzuki,2021).TRMT10A,the mammalian homolog of Trm10,incorporates N1-methylguanosine modification at position 9(m^(1)G9)of various cytoplasmic tRNAs,including tRNAGln and tRNAIniMeth(Vilardo et al.,2020).Mutations in human TRMT10A,which is enriched in pancreatic islets and brain(Igoillo-Esteve et al.,2013),are often associated with microcephaly,intellectual disability,early-onset diabetes,and short stature(Igoillo-Esteve et al.,2013;Uçan Tokuçet al.,2024).
基金the National Key Research and Development Program of China(2021YFA1100800,2020YFA0803401)the National Natural Science Foundation of China(32022040,91940302,31971230,31870811,32000919)Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine at Shanghai Tech University。
文摘TRMT1 is an N^2-methylguanosine(m^(2)G)and N^2,N^2-methylguanosine((m^(2))_(2)G)methyltransferase that targets G26 of both cytoplasmic and mitochondrial t RNAs.In higher eukaryotes,most cytoplasmic t RNAs with G26 carry(m^(2))_(2)G26,although the majority of mitochondrial G26-containing t RNAs carry m^(2)G26 or G26,suggesting differences in the mechanisms by which TRMT1 catalyzes modification of these t RNAs.Loss-of-function mutations of human TRMT1 result in neurological disorders and completely abrogate t RNA:(m^(2))_(2)G26 formation.However,the mechanism underlying the independent catalytic activity of human TRMT1 and identity of its specific substrate remain elusive,hindering a comprehensive understanding of the pathogenesis of neurological disorders caused by TRMT1 mutations.Here,we showed that human TRMT1 independently catalyzes formation of the t RNA:m^(2)G26 or(m^(2))_(2)G26 modification in a substrate-dependent manner,which explains the distinct distribution of m^(2)G26 and(m^(2))_(2)G26 on cytoplasmic and mitochondrial t RNAs.For human TRMT1-mediated t RNA:(m^(2))_(2)G26 formation,the semi-conserved C11:G24 serves as the determinant,and the U10:A25 or G10:C25 base pair is also required,while the size of the variable loop has no effect.We defined the requirements of this recognition mechanism as the“(m^(2))_(2)G26 criteria”.We found that the(m^(2))_(2)G26 modification occurred in almost all the higher eukaryotic t RNAs conforming to these criteria,suggesting the“(m^(2))_(2)G26 criteria”are applicable to other higher eukaryotic t RNAs.
基金supported by the Program of the National Natural Science Foundation of China(Nos.82171431 and 31972886)the Natural Science Fund for Distinguished Young Scholars of Hunan Province,China(Nos.2020JJ2057 and 2021JJ10074)+6 种基金Natural Science Foundation of Changsha City(No.kq2208402)the Program of the National Natural Science Foundation of Hunan Province(No.2021JJ40989)the Project Program of National Clinical Research Center for Geriatric Disorders at Xiangya Hospital(No.2020LNJJ13)the Science and Technology Innovation 2030(STI2030-Major Projects,No.2021ZD0201803)the National Key R&D Program of China(No.2021YFA0805202)the Innovation Team Project of Hunan Province(No.2019RS1010)the Innovation Team Project of Central South University(No.2020CX016).
文摘Amyotrophic lateral sclerosis(ALS)is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons,and it demonstrates high clinical heterogeneity and complex genetic architecture.A variation within TRMT2B(c.1356G>T;p.K452N)was identified to be associated with ALS in a family comprising two patients with juvenile ALS(JALS).Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS,and three more variants were identified in a public ALS database including 3317 patients with ALS.A decreased number of mitochondria,swollen mitochondria,lower expression of ND1,decreased mitochondrial complex I activities,lower mitochondrial aerobic respiration,and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells.Further,TRMT2B variations overexpression cells also displayed decreased ND1.In conclusion,a novel JALS-associated gene called TRMT2B was identified,thus broadening the clinical and genetic spectrum of ALS.
