Molecular and Cellular Biology最新文献_第8页

Correction. 修正。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-11-17 DOI: 10.1080/10985549.2023.2277100

引用次数: 0

Methyltransferase Inhibition Enables Tgfβ Driven Induction of CDKN2A and B in Cancer Cells. 甲基转移酶抑制可使 Tgfβ 在癌细胞中诱导 CDKN2A 和 B。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 DOI: 10.1080/10985549.2023.2186074

Yen-Ting Liu, Celeste Romero, Xue Xiao, Lei Guo, Xiaoyun Zhou, Mark A Applebaum, Lin Xu, Stephen X Skapek

{"title":"Methyltransferase Inhibition Enables Tgfβ Driven Induction of CDKN2A and B in Cancer Cells.","authors":"Yen-Ting Liu, Celeste Romero, Xue Xiao, Lei Guo, Xiaoyun Zhou, Mark A Applebaum, Lin Xu, Stephen X Skapek","doi":"10.1080/10985549.2023.2186074","DOIUrl":"10.1080/10985549.2023.2186074","url":null,"abstract":"CDKN2A/B deletion or silencing is common across human cancer, reinforcing the general importance of bypassing its tumor suppression in cancer formation or progression. In rhabdomyosarcoma (RMS) and neuroblastoma, two common childhood cancers, the three CDKN2A/B transcripts are independently expressed to varying degrees, but one, ARF, is uniformly silenced. Although TGFβ induces certain CDKN2A/B transcripts in HeLa cells, it was unable to do so in five tested RMS lines unless the cells were pretreated with a broadly acting methyltransferase inhibitor, DZNep, or one targeting EZH2. CDKN2A/B induction by TGFβ correlated with de novo appearance of three H3K27Ac peaks within a 20 kb cis element ∼150 kb proximal to CDKN2A/B. Deleting that segment prevented their induction by TGFβ but not a basal increase driven by methyltransferase inhibition alone. Expression of two CDKN2A/B transcripts was enhanced by dCas9/CRISPR activation targeting either the relevant promoter or the 20 kb cis elements, and this \"precise\" manipulation diminished RMS cell propagation in vitro. Our findings show crosstalk between methyltransferase inhibition and TGFβ-dependent activation of a remote enhancer to reverse CDKN2A/B silencing. Though focused on CDKN2A/B here, such crosstalk may apply to other TGFβ-responsive genes and perhaps govern this signaling protein's complex effects promoting or blocking cancer.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 3","pages":"115-129"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10038032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9646911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Degradation of CDK9 by Ubiquitin E3 Ligase STUB1 Regulates P-TEFb Level and Its Functions for Global Target Gene Expression within Mammalian Cells. 泛素E3连接酶STUB1对CDK9的降解调节P-TEFb水平及其在哺乳动物细胞内全局靶基因表达的功能。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-08-11 DOI: 10.1080/10985549.2023.2239694

Subham Basu, Arijit Nandy, Avik Ghosh, Dheerendra Pratap Mall, Debabrata Biswas

{"title":"Degradation of CDK9 by Ubiquitin E3 Ligase STUB1 Regulates P-TEFb Level and Its Functions for Global Target Gene Expression within Mammalian Cells.","authors":"Subham Basu, Arijit Nandy, Avik Ghosh, Dheerendra Pratap Mall, Debabrata Biswas","doi":"10.1080/10985549.2023.2239694","DOIUrl":"10.1080/10985549.2023.2239694","url":null,"abstract":"Positive transcription elongation factor b (P-TEFb) regulates expression of diverse sets of genes within mammalian cells that have implications in several human disease pathogeneses. However, mechanisms of functional regulation of P-TEFb complex through regulation of its stability are poorly known. In this study, we show an important role of C-terminus of Hsc70-interacting protein (CHIP aka STUB1) in regulation of overall level of CDK9 and thus P-TEFb complex within mammalian cells. STUB1 acts as a ubiquitin E3 ligase for proteasomal degradation of CDK9 involving N-terminal lysine 3 (K3) residue. Whereas, overexpression of STUB1 enhances, its knockdown reduces overall CDK9 degradation kinetics within mammalian cells. Interestingly, owing to the same region of binding within CDK9, CyclinT1 protects CDK9 from STUB1-mediated degradation. Factors that cooperatively bind with CyclinT1 to form functional complex also protects CDK9 from degradation by STUB1. Knockdown of STUB1 enhances CDK9 expression and thus P-TEFb complex formation that leads to global increase in RNA polymerase II CTD phosphorylation and transcriptional activation of diverse P-TEFb target genes. Thus, we describe an important functional role of STUB1 in regulation of transcription through modulation of overall level of P-TEFb complex formation within mammalian cells.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 9","pages":"451-471"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10512928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10294787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Fission Yeast TORC1 Promotes Cell Proliferation through Sfp1, a Transcription Factor Involved in Ribosome Biogenesis. 裂殖酵母 TORC1 通过参与核糖体生物发生的转录因子 Sfp1 促进细胞增殖

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-12-20 DOI: 10.1080/10985549.2023.2282349

Yen Teng Tai, Tomoyuki Fukuda, Yuichi Morozumi, Hayato Hirai, Arisa H Oda, Yoshiaki Kamada, Yutaka Akikusa, Tomotake Kanki, Kunihiro Ohta, Kazuhiro Shiozaki

{"title":"Fission Yeast TORC1 Promotes Cell Proliferation through Sfp1, a Transcription Factor Involved in Ribosome Biogenesis.","authors":"Yen Teng Tai, Tomoyuki Fukuda, Yuichi Morozumi, Hayato Hirai, Arisa H Oda, Yoshiaki Kamada, Yutaka Akikusa, Tomotake Kanki, Kunihiro Ohta, Kazuhiro Shiozaki","doi":"10.1080/10985549.2023.2282349","DOIUrl":"10.1080/10985549.2023.2282349","url":null,"abstract":"Target of rapamycin complex 1 (TORC1) is activated in response to nutrient availability and growth factors, promoting cellular anabolism and proliferation. To explore the mechanism of TORC1-mediated proliferation control, we performed a genetic screen in fission yeast and identified Sfp1, a zinc-finger transcription factor, as a multicopy suppressor of temperature-sensitive TORC1 mutants. Our observations suggest that TORC1 phosphorylates Sfp1 and protects Sfp1 from proteasomal degradation. Transcription analysis revealed that Sfp1 positively regulates genes involved in ribosome production together with two additional transcription factors, Ifh1/Crf1 and Fhl1. Ifh1 physically interacts with Fhl1, and the nuclear localization of Ifh1 is regulated in response to nutrient levels in a manner dependent on TORC1 and Sfp1. Taken together, our data suggest that the transcriptional regulation of the genes involved in ribosome biosynthesis by Sfp1, Ifh1, and Fhl1 is one of the key pathways through which nutrient-activated TORC1 promotes cell proliferation.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"675-692"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138487994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A PTP1B-Cdk3 Signaling Axis Promotes Cell Cycle Progression of Human Glioblastoma Cells through an Rb-E2F Dependent Pathway. PTP1B-Cdk3信号轴通过Rb-E2F依赖途径促进人胶质母细胞瘤细胞周期进程

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-12-20 DOI: 10.1080/10985549.2023.2273193

Olga Villamar-Cruz, Marco Antonio Loza-Mejía, Alonso Vivar-Sierra, Héctor Iván Saldivar-Cerón, Genaro Patiño-López, Jonadab Efraín Olguín, Luis Ignacio Terrazas, Leonel Armas-López, Federico Ávila-Moreno, Sayanti Saha, Jonathan Chernoff, Ignacio Camacho-Arroyo, Luis Enrique Arias-Romero

{"title":"A PTP1B-Cdk3 Signaling Axis Promotes Cell Cycle Progression of Human Glioblastoma Cells through an Rb-E2F Dependent Pathway.","authors":"Olga Villamar-Cruz, Marco Antonio Loza-Mejía, Alonso Vivar-Sierra, Héctor Iván Saldivar-Cerón, Genaro Patiño-López, Jonadab Efraín Olguín, Luis Ignacio Terrazas, Leonel Armas-López, Federico Ávila-Moreno, Sayanti Saha, Jonathan Chernoff, Ignacio Camacho-Arroyo, Luis Enrique Arias-Romero","doi":"10.1080/10985549.2023.2273193","DOIUrl":"10.1080/10985549.2023.2273193","url":null,"abstract":"PTP1B plays a key role in developing different types of cancer. However, the molecular mechanism underlying this effect is unclear. To identify molecular targets of PTP1B that mediate its role in tumorigenesis, we undertook a SILAC-based phosphoproteomic approach, which allowed us to identify Cdk3 as a novel PTP1B substrate. Substrate trapping experiments and docking studies revealed stable interactions between the PTP1B catalytic domain and Cdk3. In addition, we observed that PTP1B dephosphorylates Cdk3 at tyrosine residue 15 in vitro and interacts with it in human glioblastoma cells. Next, we found that pharmacological inhibition of PTP1B or its depletion with siRNA leads to cell cycle arrest with diminished activity of Cdk3, hypophosphorylation of Rb, and the downregulation of E2F target genes Cdk1, Cyclin A, and Cyclin E1. Finally, we observed that the expression of a constitutively active Cdk3 mutant bypasses the requirement of PTP1B for cell cycle progression and expression of E2F target genes. These data delineate a novel signaling pathway from PTP1B to Cdk3 required for efficient cell cycle progression in an Rb-E2F dependent manner in human GB cells.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"631-649"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138445468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Phosphorylation of the Myogenic Factor Myocyte Enhancer Factor-2 Impacts Myogenesis In Vivo. 肌生成因子-肌细胞增强因子-2的磷酸化影响体内肌生成。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-05-15 DOI: 10.1080/10985549.2023.2198167

Kumar Vishal, Elizabeth Barajas Alonso, Ashley A DeAguero, Jennifer A Waters, Maria B Chechenova, Richard M Cripps

{"title":"Phosphorylation of the Myogenic Factor Myocyte Enhancer Factor-2 Impacts Myogenesis In Vivo.","authors":"Kumar Vishal, Elizabeth Barajas Alonso, Ashley A DeAguero, Jennifer A Waters, Maria B Chechenova, Richard M Cripps","doi":"10.1080/10985549.2023.2198167","DOIUrl":"10.1080/10985549.2023.2198167","url":null,"abstract":"Activity of the myogenic regulatory protein myocyte enhancer factor-2 (MEF2) is modulated by post-translational modification. We investigated the in vivo phosphorylation of Drosophila MEF2, and identified serine 98 (S98) as a phosphorylated residue. Phospho-mimetic (S98E) and phospho-null (S98A) isoforms of MEF2 did not differ from wild-type in their activity in vitro, so we used CRISPR/Cas9 to generate an S98A allele of the endogenous gene. In mutant larvae we observed phenotypes characteristic of reduced MEF2 function, including reduced body wall muscle size and reduced expression of myofibrillar protein genes; conversely,S98A homozygotes showed enhanced MEF2 function through muscle differentiation within the adult myoblasts associated with the wing imaginal disc. In adults, S98A homozygotes were viable with normal mobility, yet showed patterning defects in muscles that were enhanced when the S98A allele was combined with a Mef2 null allele. Overall our data indicate that blocking MEF2 S98 phosphorylation in myoblasts enhances its myogenic capability, whereas blocking S98 phosphorylation in differentiating muscles attenuates MEF2 function. Our studies are among the first to assess the functional significance of MEF2 phosphorylation sites in the intact animal, and suggest that the same modification can have profoundly different effects upon MEF2 function depending upon the developmental context.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 6","pages":"241-253"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/7d/ed/TMCB_43_2198167.PMC10251773.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10176914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dematin Regulates Calcium Mobilization, Thrombosis, and Early Akt Activation in Platelets. Dematin 可调节血小板中的钙动员、血栓形成和早期 Akt 激活。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-05-22 DOI: 10.1080/10985549.2023.2210033

Daniel I Fritz, Yiwen Ding, Glenn Merrill-Skoloff, Robert Flaumenhaft, Toshihiko Hanada, Athar H Chishti

{"title":"Dematin Regulates Calcium Mobilization, Thrombosis, and Early Akt Activation in Platelets.","authors":"Daniel I Fritz, Yiwen Ding, Glenn Merrill-Skoloff, Robert Flaumenhaft, Toshihiko Hanada, Athar H Chishti","doi":"10.1080/10985549.2023.2210033","DOIUrl":"10.1080/10985549.2023.2210033","url":null,"abstract":"The complex intrinsic and extrinsic pathways contributing to platelet activation profoundly impact hemostasis and thrombosis. Detailed cellular mechanisms that regulate calcium mobilization, Akt activation, and integrin signaling in platelets remain incompletely understood. Dematin is a broadly expressed actin binding and bundling cytoskeletal adaptor protein regulated by phosphorylation via cAMP-dependent protein kinase. Here, we report the development of a conditional mouse model specifically lacking dematin in platelets. Using the new mouse model termed PDKO, we provide direct evidence that dematin is a major regulator of calcium mobilization, and its genetic deletion inhibits the early phase of Akt activation in response to collagen and thrombin agonists in platelets. The aberrant platelet shape change, clot retraction, and in vivo thrombosis observed in PDKO mice will enable future characterization of dematin-mediated integrin activation mechanisms in thrombogenic as well as nonvascular pathologies.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 6","pages":"283-299"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10251785/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9667900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Sequential Recruitments of Rab-GTPase Ypt1p and the NNS Complex onto pre-HAC1 mRNA Promote Its Nuclear Degradation in Baker's Yeast. Rab GTPase Ypt1p和NNS复合物在前HAC1 mRNA上的顺序募集促进其在贝克酵母中的核降解。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-08-02 DOI: 10.1080/10985549.2023.2227016

Sunirmal Paira, Anish Chakraborty, Biswadip Das

{"title":"The Sequential Recruitments of Rab-GTPase Ypt1p and the NNS Complex onto pre-HAC1 mRNA Promote Its Nuclear Degradation in Baker's Yeast.","authors":"Sunirmal Paira, Anish Chakraborty, Biswadip Das","doi":"10.1080/10985549.2023.2227016","DOIUrl":"10.1080/10985549.2023.2227016","url":null,"abstract":"Induction of unfolded protein response involves activation of transcription factor Hac1p that is encoded by HAC1 pre-mRNA harboring an intron and a bipartite element (BE), which is subjected to nuclear mRNA decay by the nuclear exosome/Cbc1p-Tif4631p-dependent Exosome Targeting (CTEXT) complex. Using a combination of genetic and biochemical approaches, we demonstrate that a Rab-GTPase Ypt1p controls unfolded protein response signaling dynamics. This regulation relies on the nuclear localization of a small fraction of the cellular Ypt1p pool in the absence of endoplasmic reticulum (ER)-stress causing a strong association of the nuclear Ypt1p with pre-HAC1 mRNA that eventually promotes sequential recruitments of NNS, CTEXT, and the nuclear exosome onto this pre-mRNA. Recruitment of these decay factors onto pre-HAC1 mRNA is accompanied by its rapid nuclear decay that produces a precursor RNA pool lacking functional BE thereby causing its inefficient targeting to Ire1p foci leading to their diminished splicing and translation. ER stress triggers rapid relocalization of the nuclear pool of Ypt1p to the cytoplasm leading to its dissociation from pre-HAC1 mRNA thereby causing decreased recruitment of these decay factors to precursor HAC1 RNA leading to its diminished degradation. Reduced decay results in an increased abundance of pre-HAC1 mRNA with intact functional BE leading to its enhanced recruitment to Ire1p foci.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 8","pages":"371-400"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10102467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Implications of Translesion DNA Synthesis Polymerases on Genomic Stability and Human Health. 翻译DNA合成聚合酶对基因组稳定性和人类健康的影响。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-07-13 DOI: 10.1080/10985549.2023.2224199

Jegadheeswari Venkadakrishnan, Ganesh Lahane, Arti Dhar, Wei Xiao, Krishna Moorthi Bhat, Tej K Pandita, Audesh Bhat

{"title":"Implications of Translesion DNA Synthesis Polymerases on Genomic Stability and Human Health.","authors":"Jegadheeswari Venkadakrishnan, Ganesh Lahane, Arti Dhar, Wei Xiao, Krishna Moorthi Bhat, Tej K Pandita, Audesh Bhat","doi":"10.1080/10985549.2023.2224199","DOIUrl":"10.1080/10985549.2023.2224199","url":null,"abstract":"Replication fork arrest-induced DNA double strand breaks (DSBs) caused by lesions are effectively suppressed in cells due to the presence of a specialized mechanism, commonly referred to as DNA damage tolerance (DDT). In eukaryotic cells, DDT is facilitated through translesion DNA synthesis (TLS) carried out by a set of DNA polymerases known as TLS polymerases. Another parallel mechanism, referred to as homology-directed DDT, is error-free and involves either template switching or fork reversal. The significance of the DDT pathway is well established. Several diseases have been attributed to defects in the TLS pathway, caused either by mutations in the TLS polymerase genes or dysregulation. In the event of a replication fork encountering a DNA lesion, cells switch from high-fidelity replicative polymerases to low-fidelity TLS polymerases, which are associated with genomic instability linked with several human diseases including, cancer. The role of TLS polymerases in chemoresistance has been recognized in recent years. In addition to their roles in the DDT pathway, understanding noncanonical functions of TLS polymerases is also a key to unraveling their importance in maintaining genomic stability. Here we summarize the current understanding of TLS pathway in DDT and its implication for human health.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 8","pages":"401-425"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10448981/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10425833","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Distinct Interaction Modes for the Eukaryotic RNA Polymerase Alpha-like Subunits. 真核生物 RNA 聚合酶 Alpha 类亚基的不同相互作用模式

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-05-24 DOI: 10.1080/10985549.2023.2210023

Alana E Belkevich, Haleigh G Pascual, Aula M Fakhouri, David G Ball, Bruce A Knutson

{"title":"Distinct Interaction Modes for the Eukaryotic RNA Polymerase Alpha-like Subunits.","authors":"Alana E Belkevich, Haleigh G Pascual, Aula M Fakhouri, David G Ball, Bruce A Knutson","doi":"10.1080/10985549.2023.2210023","DOIUrl":"10.1080/10985549.2023.2210023","url":null,"abstract":"Eukaryotic DNA-dependent RNA polymerases (Pols I-III) encode two distinct alpha-like heterodimers where one is shared between Pols I and III, and the other is unique to Pol II. Human alpha-like subunit mutations are associated with several diseases including Treacher Collins Syndrome (TCS), 4H leukodystrophy, and primary ovarian sufficiency. Yeast is commonly used to model human disease mutations, yet it remains unclear whether the alpha-like subunit interactions are functionally similar between yeast and human homologs. To examine this, we mutated several regions of the yeast and human small alpha-like subunits and used biochemical and genetic assays to establish the regions and residues required for heterodimerization with their corresponding large alpha-like subunits. Here we show that different regions of the small alpha-like subunits serve differential roles in heterodimerization, in a polymerase- and species-specific manner. We found that the small human alpha-like subunits are more sensitive to mutations, including a \"humanized\" yeast that we used to characterize the molecular consequence of the TCS-causingPOLR1D G52E mutation. These findings help explain why some alpha subunit associated disease mutations have little to no effect when made in their yeast orthologs and offer a better yeast model to assess the molecular basis of POLR1D associated disease mutations.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 6","pages":"269-282"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10251799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9605115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0