Destabilization of the MiniChromosome Maintenance (MCM) complex modulates the cellular response to DNA double strand breaks

Drissi, Romain; Chauvin, Anaïs; McKenna, Alyson; Lévesque, Dominique; Blais-Brochu, Simon; Jean, Dominique; Boisvert, François-Michel

doi:10.1080/15384101.2018.1553336

Cited by 23 publications

(18 citation statements)

References 64 publications

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“…In addition, the MCM complex has been shown to play a role in transcription, chromatin remodelling, and genome stability ( Bailis and Forsburg, 2004 ; Forsburg, 2004 ). More recently, MCM complex proteins have been shown to be recruited to sites of DNA damage ( Drissi et al, 2015 ) and play a role in repair responses ( Drissi et al, 2018 ). Increased MCM protein levels in the fat body of IIS mutants may aid in preventing age-related DNA damage and/or increase the efficiency of repair pathways and thus promote longevity.…”

Section: Discussionmentioning

confidence: 99%

Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Tain

Sehlke

Meilenbrock

et al. 2021

eLife

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Reduced activity of the insulin/IGF signalling network increases health during ageing in multiple species. Diverse and tissue-specific mechanisms drive the health improvement. Here, we performed tissue-specific transcriptional and proteomic profiling of long-lived Drosophila dilp2-3,5 mutants, and identified tissue-specific regulation of >3600 transcripts and >3700 proteins. Most expression changes were regulated post-transcriptionally in the fat body, and only in mutants infected with the endosymbiotic bacteria, Wolbachia pipientis, which increases their lifespan. Bioinformatic analysis identified reduced co-translational ER targeting of secreted and membrane-associated proteins and increased DNA damage/repair response proteins. Accordingly, age-related DNA damage and genome instability were lower in fat body of the mutant, and overexpression of a minichromosome maintenance protein subunit extended lifespan. Proteins involved in carbohydrate metabolism showed altered expression in the mutant intestine, and gut-specific overexpression of a lysosomal mannosidase increased autophagy, gut homeostasis, and lifespan. These processes are candidates for combatting ageing-related decline in other organisms.

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Section: Discussionmentioning

confidence: 99%

Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Tain

Sehlke

Meilenbrock

et al. 2021

eLife

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“…Interestingly, there was a significant reduction of the minichromosome maintenance (MCM) complex in UL35-expressing cells independent of poly(I:C) stimulation. The MCM complex is known to be an important factor for host DNA replication and modulates the cellular response to DNA double strand breaks [54,55]. Several HCMV proteins including IE2 [56] and pUL69 [57] target the host DNA replication machinery to force viral DNA replication.…”

Section: Discussionmentioning

confidence: 99%

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

et al. 2020

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The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.

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“…The requirement of MCM for BIR was questioned, as PIF1 helicase was found to be essential for long-range BIR 96 . However, recent evidence shows that MCM is typically recruited for unwinding DNA strands during HR and is likely needed together with PIF1 to enhance processivity 97, 98 . All these proteins are also suspected to operate during origin-independent transcription-initiated replication (TIR), a still-enigmatic mechanism that is triggered by R-loops resulting from RNA:DNA hybrids during transcription 10, 11, 99 .…”

Section: Discussionmentioning

confidence: 99%

A free-living protist that lacks canonical eukaryotic DNA replication and segregation systems

Salas‐Leiva

Tromer

Curtis

et al. 2021

Preprint

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Cells must replicate and segregate their DNA with precision. In eukaryotes, these processes are part of a regulated cell-cycle that begins at S-phase with the replication of DNA and ends after M-phase. Previous studies showed that these processes were present in the last eukaryotic common ancestor and the core parts of their molecular systems are conserved across eukaryotic diversity. However, some unicellular parasites, such as the metamonad Giardia intestinalis, have secondarily lost components of the DNA processing and segregation apparatuses. To clarify the evolutionary history of these systems in these unusual eukaryotes, we generated a high-quality draft genome assembly for the free-living metamonad Carpediemonas membranifera and carried out a comparative genomics analysis. We found that parasitic and free-living metamonads harbor a conspicuously incomplete set of canonical proteins for processing and segregating DNA. Unexpectedly, Carpediemonas species are further streamlined, completely lacking the origin recognition complex, Cdc6 and other replisome components, most structural kinetochore subunits including the Ndc80 complex, as well as several canonical cell-cycle checkpoint proteins. Carpediemonas is the first eukaryote known to have lost this large suite of conserved complexes, suggesting that it has a highly unusual cell cycle and that unlike any other known eukaryote, it must rely on a novel set of mechanisms to carry out these fundamental processes.

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Destabilization of the MiniChromosome Maintenance (MCM) complex modulates the cellular response to DNA double strand breaks

Cited by 23 publications

References 64 publications

Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

Tissue-specific modulation of gene expression in response to lowered insulin signalling in Drosophila

The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

A free-living protist that lacks canonical eukaryotic DNA replication and segregation systems

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