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Cell Communication and Signaling : CCS Sep 2023Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis.... (Review)
Review
Cells that undergo normal differentiation mainly rely on mitochondrial oxidative phosphorylation to provide energy, but most tumour cells rely on aerobic glycolysis. This phenomenon is called the "Warburg effect". Phosphoglycerate kinase 1 (PGK1) is a key enzyme in aerobic glycolysis. PGK1 is involved in glucose metabolism as well as a variety of biological activities, including angiogenesis, EMT, mediated autophagy initiation, mitochondrial metabolism, DNA replication and repair, and other processes related to tumorigenesis and development. Recently, an increasing number of studies have proven that PGK1 plays an important role in cancer. In this manuscript, we discussed the effects of the structure, function, molecular mechanisms underlying PGK1 regulation on the initiation and progression of cancer. Additionally, PGK1 is associated with chemotherapy resistance and prognosis in tumour patients. This review presents an overview of the different roles played by PGK1 during tumorigenesis, which will help in the design of experimental studies involving PGK1 and enhance the potential for the use of PGK1 as a therapeutic target in cancer. Video Abstract.
Topics: Humans; Phosphoglycerate Kinase; Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Autophagy
PubMed: 37723547
DOI: 10.1186/s12964-023-01256-4 -
MedRxiv : the Preprint Server For... Jun 2023To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate...
OBJECTIVE
To compare the frequency of replication-competent virologic rebound with and without nirmatrelvir-ritonavir treatment for acute COVID-19. Secondary aims were to estimate the validity of symptoms to detect rebound and the incidence of emergent nirmatrelvir-resistance mutations after rebound.
DESIGN
Observational cohort study.
SETTING
Multicenter healthcare system in Boston, Massachusetts.
PARTICIPANTS
We enrolled ambulatory adults with a positive COVID-19 test and/or a prescription for nirmatrelvir-ritonavir.
EXPOSURES
Receipt of 5 days of nirmatrelvir-ritonavir treatment versus no COVID-19 therapy.
MAIN OUTCOME AND MEASURES
The primary outcome was COVID-19 virologic rebound, defined as either (1) a positive SARS-CoV-2 viral culture following a prior negative culture or (2) two consecutive viral loads ≥4.0 log copies/milliliter after a prior reduction in viral load to <4.0 log copies/milliliter.
RESULTS
Compared with untreated individuals (n=55), those taking nirmatrelvir-ritonavir (n=72) were older, received more COVID-19 vaccinations, and were more commonly immunosuppressed. Fifteen individuals (20.8%) taking nirmatrelvir-ritonavir experienced virologic rebound versus one (1.8%) of the untreated (absolute difference 19.0% [95%CI 9.0-29.0%], P=0.001). In multivariable models, only N-R was associated with VR (AOR 10.02, 95%CI 1.13-88.74). VR occurred more commonly among those with earlier nirmatrelvir-ritonavir initiation (29.0%, 16.7% and 0% when initiated days 0, 1, and ≥2 after diagnosis, respectively, P=0.089). Among participants on N-R, those experiencing rebound had prolonged shedding of replication-competent virus compared to those that did not rebound (median: 14 vs 3 days). Only 8/16 with virologic rebound reported worsening symptoms (50%, 95%CI 25%-75%); 2 were completely asymptomatic. We detected no post-rebound nirmatrelvir-resistance mutations in the NSP5 protease gene.
CONCLUSIONS AND RELEVANCE
Virologic rebound occurred in approximately one in five people taking nirmatrelvir-ritonavir and often occurred without worsening symptoms. Because it is associated with replication-competent viral shedding, close monitoring and potential isolation of those who rebound should be considered.
PubMed: 37425934
DOI: 10.1101/2023.06.23.23288598 -
Nucleic Acids Research Aug 2023The discovery of reverse transcriptases (RTs) challenged the central dogma by establishing that genetic information can also flow from RNA to DNA. Although they act as...
The discovery of reverse transcriptases (RTs) challenged the central dogma by establishing that genetic information can also flow from RNA to DNA. Although they act as DNA polymerases, RTs are distantly related to replicases that also possess de novo primase activity. Here we identify that CRISPR associated RTs (CARTs) directly prime DNA synthesis on both RNA and DNA. We demonstrate that RT-dependent priming is utilized by some CRISPR-Cas complexes to synthesise new spacers and integrate these into CRISPR arrays. Expanding our analyses, we show that primer synthesis activity is conserved in representatives of other major RT classes, including group II intron RT, telomerase and retroviruses. Together, these findings establish a conserved innate ability of RTs to catalyse de novo DNA primer synthesis, independently of accessory domains or alternative priming mechanisms, which likely plays important roles in a wide variety of biological pathways.
Topics: DNA-Directed DNA Polymerase; HIV Reverse Transcriptase; Introns; Retroviridae; RNA; RNA-Directed DNA Polymerase; DNA Replication
PubMed: 37279911
DOI: 10.1093/nar/gkad478 -
Frontiers in Microbiology 2023Influenza viruses are one of the major causes of human respiratory infections and the newly emerging and re-emerging strains of influenza virus are the cause of seasonal... (Review)
Review
Influenza viruses are one of the major causes of human respiratory infections and the newly emerging and re-emerging strains of influenza virus are the cause of seasonal epidemics and occasional pandemics, resulting in a huge threat to global public health systems. As one of the early immune cells can rapidly recognize and respond to influenza viruses in the respiratory, lung macrophages play an important role in controlling the severity of influenza disease by limiting viral replication, modulating the local inflammatory response, and initiating subsequent adaptive immune responses. However, influenza virus reproduction in macrophages is both strain- and macrophage type-dependent, and ineffective replication of some viral strains in mouse macrophages has been observed. This review discusses the function of lung macrophages in influenza virus infection in order to better understand the pathogenesis of the influenza virus.
PubMed: 37779697
DOI: 10.3389/fmicb.2023.1260543 -
Molecular Cell Aug 2023Homologous recombination (HR) is essential for error-free repair of DNA double-strand breaks, perturbed replication forks (RFs), and post-replicative single-stranded DNA...
Homologous recombination (HR) is essential for error-free repair of DNA double-strand breaks, perturbed replication forks (RFs), and post-replicative single-stranded DNA (ssDNA) gaps. To initiate HR, the recombination mediator and tumor suppressor protein BRCA2 facilitates nucleation of RAD51 on ssDNA prior to stimulation of RAD51 filament growth by RAD51 paralogs. Although ssDNA binding by BRCA2 has been implicated in RAD51 nucleation, the function of double-stranded DNA (dsDNA) binding by BRCA2 remains unclear. Here, we exploit single-molecule (SM) imaging to visualize BRCA2-mediated RAD51 nucleation in real time using purified proteins. We report that BRCA2 nucleates and stabilizes RAD51 on ssDNA either directly or through an unappreciated diffusion-assisted delivery mechanism involving binding to and sliding along dsDNA, which requires the cooperative action of multiple dsDNA-binding modules in BRCA2. Collectively, our work reveals two distinct mechanisms of BRCA2-dependent RAD51 loading onto ssDNA, which we propose are critical for its diverse functions in maintaining genome stability and cancer suppression.
Topics: Humans; BRCA2 Protein; Rad51 Recombinase; DNA-Binding Proteins; DNA, Single-Stranded; DNA; DNA Repair; Protein Binding
PubMed: 37499663
DOI: 10.1016/j.molcel.2023.06.031 -
Cells Nov 2023Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I),... (Review)
Review
Mature hepatocytes (MHs) in an adult rodent liver are categorized into the following three subpopulations based on their proliferative capability: type I cells (MH-I), which are committed progenitor cells that possess a high growth capability and basal hepatocytic functions; type II cells (MH-II), which possess a limited proliferative capability; and type III cells (MH-III), which lose the ability to divide (replicative senescence) and reach the final differentiated state. These subpopulations may explain the liver's development and growth after birth. Generally, small-sized hepatocytes emerge in mammal livers. The cells are characterized by being morphologically identical to hepatocytes except for their size, which is substantially smaller than that of ordinary MHs. We initially discovered small hepatocytes (SHs) in the primary culture of rat hepatocytes. We believe that SHs are derived from MH-I and play a role as hepatocytic progenitors to supply MHs. The population of MH-I (SHs) is distributed in the whole lobules, a part of which possesses a self-renewal capability, and decreases with age. Conversely, injured livers of experimental models and clinical cases showed the emergence of SHs. Studies demonstrate the involvement of SHs in liver regeneration. SHs that appeared in the injured livers are not a pure population but a mixture of two distinct origins, MH-derived and hepatic-stem-cell-derived cells. The predominant cell-derived SHs depend on the proliferative capability of the remaining MHs after the injury. This review will focus on the SHs that appeared in the liver and discuss the significance of SHs in liver regeneration.
Topics: Rats; Animals; Rats, Inbred F344; Liver; Hepatocytes; Cell Differentiation; Stem Cells; Mammals
PubMed: 38067145
DOI: 10.3390/cells12232718 -
The EMBO Journal Sep 2023CMG (Cdc45-MCM-GINS) helicase assembly at the replication origin is the culmination of eukaryotic DNA replication initiation. This process can be reconstructed in vitro...
CMG (Cdc45-MCM-GINS) helicase assembly at the replication origin is the culmination of eukaryotic DNA replication initiation. This process can be reconstructed in vitro using defined factors in Saccharomyces cerevisiae; however, in vertebrates, origin-dependent CMG formation has not yet been achieved partly due to the lack of a complete set of known initiator proteins. Since a microcephaly gene product, DONSON, was reported to remodel the CMG helicase under replication stress, we analyzed its role in DNA replication using a Xenopus cell-free system. We found that DONSON was essential for the replisome assembly. In vertebrates, DONSON physically interacted with GINS and Polε via its conserved N-terminal PGY and NPF motifs, and the DONSON-GINS interaction contributed to the replisome assembly. DONSON's chromatin association during replication initiation required the pre-replicative complex, TopBP1, and kinase activities of S-CDK and DDK. Both S-CDK and DDK required DONSON to trigger replication initiation. Moreover, human DONSON could substitute for the Xenopus protein in a cell-free system. These findings indicate that vertebrate DONSON is a novel initiator protein essential for CMG helicase assembly.
Topics: Animals; Humans; Minichromosome Maintenance Proteins; Cell Cycle Proteins; DNA-Binding Proteins; Saccharomyces cerevisiae Proteins; DNA Replication; Saccharomyces cerevisiae; Vertebrates
PubMed: 37458194
DOI: 10.15252/embj.2023114131 -
The EMBO Journal Sep 2023The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we...
The conserved protein HMCES crosslinks to abasic (AP) sites in ssDNA to prevent strand scission and the formation of toxic dsDNA breaks during replication. Here, we report a non-proteolytic release mechanism for HMCES-DNA-protein crosslinks (DPCs), which is regulated by DNA context. In ssDNA and at ssDNA-dsDNA junctions, HMCES-DPCs are stable, which efficiently protects AP sites against spontaneous incisions or cleavage by APE1 endonuclease. In contrast, HMCES-DPCs are released in dsDNA, allowing APE1 to initiate downstream repair. Mechanistically, we show that release is governed by two components. First, a conserved glutamate residue, within HMCES' active site, catalyses reversal of the crosslink. Second, affinity to the underlying DNA structure determines whether HMCES re-crosslinks or dissociates. Our study reveals that the protective role of HMCES-DPCs involves their controlled release upon bypass by replication forks, which restricts DPC formation to a necessary minimum.
Topics: DNA; Proteins; DNA Damage; DNA, Single-Stranded; DNA Repair
PubMed: 37519246
DOI: 10.15252/embj.2022113360 -
Microbiology (Reading, England) Dec 2023In this primer on biofilms and their role in infections, we trace the historical roots of microbial understanding from Van Leeuwenhoek's observations to Bill Costerton's...
In this primer on biofilms and their role in infections, we trace the historical roots of microbial understanding from Van Leeuwenhoek's observations to Bill Costerton's groundbreaking work, which solidified biofilms' significance in infections. biofilm research, investigating patient samples and utilizing diverse host models, has yielded invaluable insights into these complex microbial communities. However, it comes with several challenges, particularly regarding replicating biofilm infections accurately in the laboratory. biofilm analyses involve various techniques, revealing biofilm architecture, composition, and behaviour, while gaps in knowledge persist regarding infection initiation and source, diversity, and the Infectious Microenvironment (IME). Ultimately, the study of biofilms in infections remains a dynamic and evolving field poised to transform our approach to combat biofilm-associated diseases.
Topics: Humans; Biofilms; Infections
PubMed: 38050845
DOI: 10.1099/mic.0.001407