The posttranscriptional addition of nontemplated nucleotides to the 3′ ends of RNA molecules can have a significant impact on their stability and biological function. It has been recently discovered that nontemplated...The posttranscriptional addition of nontemplated nucleotides to the 3′ ends of RNA molecules can have a significant impact on their stability and biological function. It has been recently discovered that nontemplated addition of uridine or adenosine to the 3′ ends of RNAs occurs in different organisms ranging from algae to humans, and on different kinds of RNAs, such as histone m RNAs, m RNA fragments, U6 sn RNA, mature small RNAs and their precursors etc. These modifications may lead to different outcomes, such as increasing RNA decay, promoting or inhibiting RNA processing, or changing RNA activity. Growing pieces of evidence have revealed that such modifications can be RNA sequence-specific and subjected to temporal or spatial regulation in development. RNA tailing and its outcomes have been associated with human diseases such as cancer. Here, we review recent developments in RNA uridylation and adenylation and discuss the future prospects in this research area.展开更多
Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a gr...Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called "Adenylate-Uridylate-rich elements binding proteins"(AUBPs)control mRNA stability or translation through their binding to AU-rich elements enriched in the 3'UTRs of inflammation-and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules(also known as P-body/SG). Alterations in the expression and activities of AUBPs and Pbody/SG assembly have been observed to occur with colorectal cancer(CRC)progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis.Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation,along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.展开更多
Galactosemia is an autosomal recessive disorder caused by deficient or absent activities of one of the three enzymes involved in the galactose metabolic pathway. The predominant form is classic type galactosemia cause...Galactosemia is an autosomal recessive disorder caused by deficient or absent activities of one of the three enzymes involved in the galactose metabolic pathway. The predominant form is classic type galactosemia caused by severe reduction or absence of the galactose- 1-phosphate uridyl transferase (GALT) enzyme. Coexistence of extrahepatic biliary atresia (EHBA) with Duarte 1 and 2 variants of galactosemia has not been described earlier. Here we report a case of EHBA with concordant Duarte 1 and 2 variants of galactosemia in an infant with cholestasis. Genetic analysis of the index patient for galactosemia revealed presence of Duarte 1/Duarte 2 variants of galactosemia with genotype N314D-L218L/N314D-G1105C-GI391A- G1323A-5’UTR-119delGTCA. Clinical evaluation of the patient showed the presence of EHBA. Henceforth, it may be hypothesized that EHBA may have a genetic basis with simultaneous involvement of the GALT gene.展开更多
Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabdit...Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans.Canonical s RNAs in C.elegans are mi RNAs,small interfering RNAs including 22G-RNAs and 26G-RNAs,and 21U-RNAs,which are C.elegans pi RNAs.Previous studies have only covered some of these Argonautes for their s RNA partners,and thus,a systematic study is needed to reveal the comprehensive regulatory networks formed by C.elegans Argonautes and their associated s RNAs.We obtained in situ knockin(KI)strains of all C.elegans Argonautes with fusion tags by CRISPR/Cas9 technology.RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the s RNA profiles of individual Argonautes.The s RNA partners for each Argonaute were then analyzed.We found that there were 10Argonautes enriched mi RNAs,17 Argonautes bound to 22G-RNAs,8 Argonautes bound to 26G-RNAs,and 1 Argonaute PRG-1bound to pi RNAs.Uridylated 22G-RNAs were bound by four Argonautes HRDE-1,WAGO-4,CSR-1,and PPW-2.We found that all four Argonautes played a role in transgenerational epigenetic inheritance.Regulatory roles of the corresponding Argonaute-s RNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated.In this study,we portrayed the s RNAs bound to each functional Argonaute in C.elegans.Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C.elegans Argonautes and s RNAs.The s RNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.展开更多
基金supported by the National Institutes of Health(GM061146)National Science Foundation(IOS-1340001)the National Natural Science Foundation of China(91440105 and 31571332)
文摘The posttranscriptional addition of nontemplated nucleotides to the 3′ ends of RNA molecules can have a significant impact on their stability and biological function. It has been recently discovered that nontemplated addition of uridine or adenosine to the 3′ ends of RNAs occurs in different organisms ranging from algae to humans, and on different kinds of RNAs, such as histone m RNAs, m RNA fragments, U6 sn RNA, mature small RNAs and their precursors etc. These modifications may lead to different outcomes, such as increasing RNA decay, promoting or inhibiting RNA processing, or changing RNA activity. Growing pieces of evidence have revealed that such modifications can be RNA sequence-specific and subjected to temporal or spatial regulation in development. RNA tailing and its outcomes have been associated with human diseases such as cancer. Here, we review recent developments in RNA uridylation and adenylation and discuss the future prospects in this research area.
基金Supported by the National Institutes of Health/National Cancer Institute Cancer Center Support grant P30 CA168524(DD)supported by a grant of the Geneva Cancer League(Grant no.1711)
文摘Trans-acting factors controlling mRNA fate are critical for the post-transcriptional regulation of inflammation-related genes, as well as for oncogene and tumor suppressor expression in human cancers. Among them, a group of RNA-binding proteins called "Adenylate-Uridylate-rich elements binding proteins"(AUBPs)control mRNA stability or translation through their binding to AU-rich elements enriched in the 3'UTRs of inflammation-and cancer-associated mRNA transcripts. AUBPs play a central role in the recruitment of target mRNAs into small cytoplasmic foci called Processing-bodies and stress granules(also known as P-body/SG). Alterations in the expression and activities of AUBPs and Pbody/SG assembly have been observed to occur with colorectal cancer(CRC)progression, indicating the significant role AUBP-dependent post-transcriptional regulation plays in controlling gene expression during CRC tumorigenesis.Accordingly, these alterations contribute to the pathological expression of many early-response genes involved in prostaglandin biosynthesis and inflammation,along with key oncogenic pathways. In this review, we summarize the current role of these proteins in CRC development. CRC remains a major cause of cancer mortality worldwide and, therefore, targeting these AUBPs to restore efficient post-transcriptional regulation of gene expression may represent an appealing therapeutic strategy.
文摘Galactosemia is an autosomal recessive disorder caused by deficient or absent activities of one of the three enzymes involved in the galactose metabolic pathway. The predominant form is classic type galactosemia caused by severe reduction or absence of the galactose- 1-phosphate uridyl transferase (GALT) enzyme. Coexistence of extrahepatic biliary atresia (EHBA) with Duarte 1 and 2 variants of galactosemia has not been described earlier. Here we report a case of EHBA with concordant Duarte 1 and 2 variants of galactosemia in an infant with cholestasis. Genetic analysis of the index patient for galactosemia revealed presence of Duarte 1/Duarte 2 variants of galactosemia with genotype N314D-L218L/N314D-G1105C-GI391A- G1323A-5’UTR-119delGTCA. Clinical evaluation of the patient showed the presence of EHBA. Henceforth, it may be hypothesized that EHBA may have a genetic basis with simultaneous involvement of the GALT gene.
基金supported by the National Key Research and Development Program of China (2019YFA0802600)the National Natural Science Foundation of China (31930019,31900442,32200431)+1 种基金the Strategic Priority Research Program“Biological basis of aging and therapeutic strategies”of the Chinese Academy of Sciences (XDB39010400)the China Postdoctoral Science Foundation (2022M713053)。
文摘Argonaute proteins generally play regulatory roles by forming complexes with the corresponding small RNAs(s RNAs).An expanded Argonaute family with 20 potentially functional members has been identified in Caenorhabditis elegans.Canonical s RNAs in C.elegans are mi RNAs,small interfering RNAs including 22G-RNAs and 26G-RNAs,and 21U-RNAs,which are C.elegans pi RNAs.Previous studies have only covered some of these Argonautes for their s RNA partners,and thus,a systematic study is needed to reveal the comprehensive regulatory networks formed by C.elegans Argonautes and their associated s RNAs.We obtained in situ knockin(KI)strains of all C.elegans Argonautes with fusion tags by CRISPR/Cas9 technology.RNA immunoprecipitation against these endogenously expressed Argonautes and high-throughput sequencing acquired the s RNA profiles of individual Argonautes.The s RNA partners for each Argonaute were then analyzed.We found that there were 10Argonautes enriched mi RNAs,17 Argonautes bound to 22G-RNAs,8 Argonautes bound to 26G-RNAs,and 1 Argonaute PRG-1bound to pi RNAs.Uridylated 22G-RNAs were bound by four Argonautes HRDE-1,WAGO-4,CSR-1,and PPW-2.We found that all four Argonautes played a role in transgenerational epigenetic inheritance.Regulatory roles of the corresponding Argonaute-s RNA complex in managing levels of long transcripts and interspecies regulation were also demonstrated.In this study,we portrayed the s RNAs bound to each functional Argonaute in C.elegans.Bioinformatics analyses together with experimental investigations provided perceptions in the overall view of the regulatory network formed by C.elegans Argonautes and s RNAs.The s RNA profiles bound to individual Argonautes reported here will be valuable resources for further studies.
