Molecular and Cellular Biology最新文献_第9页

Chaperone-Dependent Degradation of Cdc42 Promotes Cell Polarity and Shields the Protein from Aggregation. 蛋白伴侣依赖性降解 Cdc42 可促进细胞极性并防止蛋白质聚集。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-04-28 DOI: 10.1080/10985549.2023.2198171

Beatriz González, Martí Aldea, Paul J Cullen

{"title":"Chaperone-Dependent Degradation of Cdc42 Promotes Cell Polarity and Shields the Protein from Aggregation.","authors":"Beatriz González, Martí Aldea, Paul J Cullen","doi":"10.1080/10985549.2023.2198171","DOIUrl":"10.1080/10985549.2023.2198171","url":null,"abstract":"Rho GTPases are global regulators of cell polarity and signaling. By exploring the turnover regulation of the yeast Rho GTPase Cdc42p, we identified new regulatory features surrounding the stability of the protein. We specifically show that Cdc42p is degraded at 37 °C by chaperones through lysine residues located in the C-terminus of the protein. Cdc42p turnover at 37 °C occurred by the 26S proteasome in an ESCRT-dependent manner in the lysosome/vacuole. By analyzing versions of Cdc42p that were defective for turnover, we show that turnover at 37 °C promoted cell polarity but was defective for sensitivity to mating pheromone, presumably mediated through a Cdc42p-dependent MAP kinase pathway. We also identified one residue (K16) in the P-loop of the protein that was critical for Cdc42p stability. Accumulation of Cdc42pK16R in some contexts led to the formation of protein aggregates, which were enriched in aging mother cells and cells undergoing proteostatic stress. Our study uncovers new aspects of protein turnover regulation of a Rho-type GTPase that may extend to other systems. Moreover, residues identified here that mediate Cdc42p turnover correlate with several human diseases, which may suggest that turnover regulation of Cdc42p is important to aspects of human health.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 5","pages":"200-222"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10184603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9510794","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

Shared Gene Targets of the ATF4 and p53 Transcriptional Networks. ATF4和p53转录网络的共享基因靶点。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-08-02 DOI: 10.1080/10985549.2023.2229225

Gabriele Baniulyte, Serene A Durham, Lauren E Merchant, Morgan A Sammons

{"title":"Shared Gene Targets of the ATF4 and p53 Transcriptional Networks.","authors":"Gabriele Baniulyte, Serene A Durham, Lauren E Merchant, Morgan A Sammons","doi":"10.1080/10985549.2023.2229225","DOIUrl":"10.1080/10985549.2023.2229225","url":null,"abstract":"The master tumor suppressor p53 regulates multiple cell fate decisions, such as cell cycle arrest and apoptosis, via transcriptional control of a broad gene network. Dysfunction in the p53 network is common in cancer, often through mutations that inactivate p53 or other members of the pathway. Induction of tumor-specific cell death by restoration of p53 activity without off-target effects has gained significant interest in the field. In this study, we explore the gene regulatory mechanisms underlying a putative anticancer strategy involving stimulation of the p53-independent integrated stress response (ISR). Our data demonstrate the p53 and ISR pathways converge to independently regulate common metabolic and proapoptotic genes. We investigated the architecture of multiple gene regulatory elements bound by p53 and the ISR effector ATF4 controlling this shared regulation. We identified additional key transcription factors that control basal and stress-induced regulation of these shared p53 and ATF4 target genes. Thus, our results provide significant new molecular and genetic insight into gene regulatory networks and transcription factors that are the target of numerous antitumor therapies.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 8","pages":"426-449"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/ec/fa/TMCB_43_2229225.PMC10448979.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10426326","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

Persistent Acetylation of Histone H3 Lysine 56 Compromises the Activity of DNA Replication Origins. 组蛋白H3赖氨酸56的持续乙酰化损害DNA复制起源的活性。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-11-17 DOI: 10.1080/10985549.2023.2259739

Roch Tremblay, Yosra Mehrjoo, Oumaima Ahmed, Antoine Simoneau, Mary E McQuaid, El Bachir Affar, Corey Nislow, Guri Giaever, Hugo Wurtele

{"title":"Persistent Acetylation of Histone H3 Lysine 56 Compromises the Activity of DNA Replication Origins.","authors":"Roch Tremblay, Yosra Mehrjoo, Oumaima Ahmed, Antoine Simoneau, Mary E McQuaid, El Bachir Affar, Corey Nislow, Guri Giaever, Hugo Wurtele","doi":"10.1080/10985549.2023.2259739","DOIUrl":"10.1080/10985549.2023.2259739","url":null,"abstract":"In Saccharomyces cerevisiae, newly synthesized histones H3 are acetylated on lysine 56 (H3 K56ac) by the Rtt109 acetyltransferase prior to their deposition on nascent DNA behind replication forks. Two deacetylases of the sirtuin family, Hst3 and Hst4, remove H3 K56ac from chromatin after S phase. hst3Δ hst4Δ cells present constitutive H3 K56ac, which sensitizes cells to replicative stress via unclear mechanisms. A chemogenomic screen revealed that DBF4 heterozygosity sensitizes cells to NAM-induced inhibition of sirtuins. DBF4 and CDC7 encode subunits of the Dbf4-dependent kinase (DDK), which activates origins of DNA replication during S phase. We show that (i) cells harboring the dbf4-1 or cdc7-4 hypomorphic alleles are sensitized to NAM, and that (ii) the sirtuins Sir2, Hst1, Hst3, and Hst4 promote DNA replication in cdc7-4 cells. We further demonstrate that Rif1, an inhibitor of DDK-dependent activation of origins, causes DNA damage and replication defects in NAM-treated cells and hst3Δ hst4Δ mutants. cdc7-4 hst3Δ hst4Δ cells are shown to display delayed initiation of DNA replication, which is not due to intra-S checkpoint activation but requires Rtt109-dependent H3 K56ac. Our results suggest that constitutive H3 K56ac sensitizes cells to replicative stress in part by negatively influencing the activation of origins of DNA replication.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"566-595"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10791153/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41127303","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

Functional Consequences of Shifting Transcript Boundaries in Glucose Starvation. 葡萄糖饥饿中转录边界转移的功能后果。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-11-17 DOI: 10.1080/10985549.2023.2270406

Lan Anh Catherine Nguyen, Masaru Mori, Yuji Yasuda, Josephine Galipon

{"title":"Functional Consequences of Shifting Transcript Boundaries in Glucose Starvation.","authors":"Lan Anh Catherine Nguyen, Masaru Mori, Yuji Yasuda, Josephine Galipon","doi":"10.1080/10985549.2023.2270406","DOIUrl":"10.1080/10985549.2023.2270406","url":null,"abstract":"Glucose is a major source of carbon and essential for the survival of many organisms, ranging from yeast to human. A sudden 60-fold reduction of glucose in exponentially growing fission yeast induces transcriptome-wide changes in gene expression. This regulation is multilayered, and the boundaries of transcripts are known to vary, with functional consequences at the protein level. By combining direct RNA sequencing with 5'-CAGE and short-read sequencing, we accurately defined the 5'- and 3'-ends of transcripts that are both poly(A) tailed and 5'-capped in glucose starvation, followed by proteome analysis. Our results confirm previous experimentally validated loci with alternative isoforms and reveal several transcriptome-wide patterns. First, we show that sense-antisense gene pairs are more strongly anticorrelated when a time lag is taken into account. Second, we show that the glucose starvation response initially elicits a shortening of 3'-UTRs and poly(A) tails, followed by a shortening of the 5'-UTRs at later time points. These result in domain gains and losses in proteins involved in the stress response. Finally, the relatively poor overlap both between differentially expressed genes (DEGs), differential transcript usage events (DTUs), and differentially detected proteins (DDPs) highlight the need for further study on post-transcriptional regulation mechanisms in glucose starvation.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"611-628"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71483578","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

Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants. 通过基因和药物调节细胞蛋白稳态可部分修复高胱氨酸尿症致病胱硫醚-β合成酶变异体的功能。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-12-20 DOI: 10.1080/10985549.2023.2284147

Renata Collard, Tomas Majtan

{"title":"Genetic and Pharmacological Modulation of Cellular Proteostasis Leads to Partial Functional Rescue of Homocystinuria-Causing Cystathionine-Beta Synthase Variants.","authors":"Renata Collard, Tomas Majtan","doi":"10.1080/10985549.2023.2284147","DOIUrl":"10.1080/10985549.2023.2284147","url":null,"abstract":"Homocystinuria (HCU), an inherited metabolic disorder caused by lack of cystathionine beta-synthase (CBS) activity, is chiefly caused by misfolding of single amino acid residue missense pathogenic variants. Previous studies showed that chemical, pharmacological chaperones or proteasome inhibitors could rescue function of multiple pathogenic CBS variants; however, the underlying mechanisms remain poorly understood. Using Chinese hamster DON fibroblasts devoid of CBS and stably overexpressing human WT or mutant CBS, we showed that expression of pathogenic CBS variant mostly dysregulates gene expression of small heat shock proteins HSPB3 and HSPB8 and members of HSP40 family. Endoplasmic reticulum stress sensor BiP was found upregulated with CBS I278T variant associated with proteasomes suggesting proteotoxic stress and degradation of misfolded CBS. Co-expression of the main effector HSP70 or master regulator HSF1 rescued steady-state levels of CBS I278T and R125Q variants with partial functional rescue of the latter. Pharmacological proteostasis modulators partially rescued expression and activity of CBS R125Q likely due to reduced proteotoxic stress as indicated by decreased BiP levels and promotion of refolding as indicated by induction of HSP70. In conclusion, targeted manipulation of cellular proteostasis may represent a viable therapeutic approach for the permissive pathogenic CBS variants causing HCU.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"664-674"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10761163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138487995","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

Correction. 更正。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-12-20 DOI: 10.1080/10985549.2023.2289812

引用次数: 0

Correction. 修正。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-12-20 DOI: 10.1080/10985549.2023.2279475

引用次数: 0

Hsp70 Binding to the N-terminal Domain of Hsp104 Regulates [PSI⁺] Curing by Hsp104 Overexpression. Hsp70与Hsp104 N-末端结构域的结合通过Hsp104过表达调控[PSI+]固化。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-04-26 DOI: 10.1080/10985549.2023.2198181

Xiaohong Zhao, Katherine Stanford, Joseph Ahearn, Daniel C Masison, Lois E Greene

{"title":"Hsp70 Binding to the N-terminal Domain of Hsp104 Regulates [PSI+] Curing by Hsp104 Overexpression.","authors":"Xiaohong Zhao, Katherine Stanford, Joseph Ahearn, Daniel C Masison, Lois E Greene","doi":"10.1080/10985549.2023.2198181","DOIUrl":"10.1080/10985549.2023.2198181","url":null,"abstract":"Hsp104 propagates the yeast prion [PSI+], the infectious form of Sup35, by severing the prion seeds, but when Hsp104 is overexpressed, it cures [PSI+] in a process that is not yet understood but may be caused by trimming, which removes monomers from the ends of the amyloid fibers. This curing was shown to depend on both the N-terminal domain of Hsp104 and the expression level of various members of the Hsp70 family, which raises the question as to whether these effects of Hsp70 are due to it binding to the Hsp70 binding site that was identified in the N-terminal domain of Hsp104, a site not involved in prion propagation. Investigating this question, we now find, first, that mutating this site prevents both the curing of [PSI+] by Hsp104 overexpression and the trimming activity of Hsp104. Second, we find that depending on the specific member of the Hsp70 family binding to the N-terminal domain of Hsp104, both trimming and the curing caused by Hsp104 overexpression are either increased or decreased in parallel. Therefore, the binding of Hsp70 to the N-terminal domain of Hsp104 regulates both the rate of [PSI+] trimming by Hsp104 and the rate of [PSI+] curing by Hsp104 overexpression.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 4","pages":"157-173"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10153015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9462565","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

Recruitment of RBM6 to DNA Double-Strand Breaks Fosters Homologous Recombination Repair. RBM6 在 DNA 双股断裂处的招募促进了同源重组修复。

IF 5.3 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 DOI: 10.1080/10985549.2023.2187105

Samah W Awwad, Malak M Darawshe, Feras E Machour, Inbar Arman, Nabieh Ayoub

{"title":"Recruitment of RBM6 to DNA Double-Strand Breaks Fosters Homologous Recombination Repair.","authors":"Samah W Awwad, Malak M Darawshe, Feras E Machour, Inbar Arman, Nabieh Ayoub","doi":"10.1080/10985549.2023.2187105","DOIUrl":"10.1080/10985549.2023.2187105","url":null,"abstract":"DNA double-strand breaks (DSBs) are highly toxic lesions that threaten genome integrity and cell survival. To avoid harmful repercussions of DSBs, a wide variety of DNA repair factors are recruited to execute DSB repair. Previously, we demonstrated that RBM6 splicing factor facilitates homologous recombination (HR) of DSB by regulating alternative splicing-coupled nonstop-decay of the HR protein APBB1/Fe65. Here, we describe a splicing-independent function of RBM6 in promoting HR repair of DSBs. We show that RBM6 is recruited to DSB sites and PARP1 activity indirectly regulates RBM6 recruitment to DNA breakage sites. Deletion mapping analysis revealed a region containing five glycine residues within the G-patch domain that regulates RBM6 accumulation at DNA damage sites. We further ascertain that RBM6 interacts with Rad51, and this interaction is attenuated in RBM6 mutant lacking the G-patch domain (RBM6del(G-patch)). Consequently, RBM6del(G-patch) cells exhibit reduced levels of Rad51 foci after ionizing radiation. In addition, while RBM6 deletion mutant lacking the G-patch domain has no detectable effect on the expression levels of its splicing targets Fe65 and Eya2, it fails to restore the integrity of HR. Altogether, our results suggest that RBM6 recruitment to DSB promotes HR repair, irrespective of its splicing activity.HIGHLIGHTSPARP1 activity indirectly regulates RBM6 recruitment to DNA damage sites.Five glycine residues within the G-patch domain of RBM6 are critical for its recruitment to DNA damage sites, but dispensable for its splicing activity.RBM6 G-patch domain fosters its interaction with Rad51 and promotes Rad51 foci formation following irradiation.RBM6 recruitment to DSB sites underpins HR repair.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":"43 3","pages":"130-142"},"PeriodicalIF":5.3,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10038030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9646913","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

Transcription Repression of CRY2 via PER2 Interaction Promotes Adipogenesis. 通过PER2相互作用抑制CRY2的转录促进脂肪生成。

IF 3.2 2区生物学

Molecular and Cellular Biology Pub Date : 2023-01-01 Epub Date: 2023-10-11 DOI: 10.1080/10985549.2023.2253710

Weini Li, Xuekai Xiong, Tali Kiperman, Ke Ma

{"title":"Transcription Repression of CRY2 via PER2 Interaction Promotes Adipogenesis.","authors":"Weini Li, Xuekai Xiong, Tali Kiperman, Ke Ma","doi":"10.1080/10985549.2023.2253710","DOIUrl":"10.1080/10985549.2023.2253710","url":null,"abstract":"The circadian clock is driven by a transcriptional-translational feedback loop, and cryptochrome 2 (CRY2) represses CLOCK/BMAL1-induced transcription activation. Despite the established role of clock in adipogenic regulation, whether the CRY2 repressor activity functions in adipocyte biology remains unclear. Here we identify a critical cysteine residue of CRY2 that mediates interaction with Period 2 (PER2). We further demonstrate that this mechanism is required for repressing circadian clock-controlled Wnt signaling to promote adipogenesis. CRY2 protein is enriched in white adipose depots and robustly induced by adipogenic differentiation. Via site-directed mutagenesis, we identified that a conserved CRY2 cysteine at 432 within the loop interfacing with PER2 mediates heterodimer complex formation that confers transcription repression. C432 mutation disrupted PER2 association without affecting BMAL1 binding, leading to loss of repression of clock transcription activation. In preadipocytes, whereas CRY2 enhanced adipocyte differentiation, the repression-defective C432 mutant suppressed this process. Furthermore, silencing of CRY2 attenuated, while stabilization of CRY2 by KL001 markedly augmented adipocyte maturation. Mechanistically, we show that transcriptional repression of Wnt pathway components underlies CRY2 modulation of adipogenesis. Collectively, our findings elucidate a CRY2-mediated repression mechanism that promotes adipocyte development, and implicate its potential as a clock intervention target for obesity.","PeriodicalId":18658,"journal":{"name":"Molecular and Cellular Biology","volume":" ","pages":"500-514"},"PeriodicalIF":3.2,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10569361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41151058","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