Dicer prevents genome instability in response to replication stress

Fragkos, Michalis; Barra, Viviana; Egger, Tom; Bordignon, Benoît; Lemaçon, Delphine; Naim, Valeria; Coquelle, Arnaud

doi:10.18632/oncotarget.27034

Cited by 14 publications

(9 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Homologous recombination (HR) factors such as RAD51, BRCA1 and BRCA2 and members of the FA pathway, disabled in the chromosome instability and cancer predisposition syndrome Fanconi anemia, are central regulators of replication stress tolerance through their functions in replication fork protection, which are distinct from their canonical roles in the HR-mediated repair of collapsed forks [63]. Following replication stress, the recruitment of the FA protein FANCD2 and of TOPBP1 to stalled forks is promoted by the microRNA pathway enzymes Dicer and Drosha, which foster the activation of the ATR-dependent S phase checkpoint and limit cells with under-replicated DNA from proceeding into mitosis [64].…”

Section: Mechanisms Protecting Against Replication Stress and Under-rmentioning

confidence: 99%

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Wilhelm

Said

Naim

2020

Genes

Self Cite

105

View full text Add to dashboard Cite

Chromosomal instability (CIN) is associated with many human diseases, including neurodevelopmental or neurodegenerative conditions, age-related disorders and cancer, and is a key driver for disease initiation and progression. A major source of structural chromosome instability (s-CIN) leading to structural chromosome aberrations is “replication stress”, a condition in which stalled or slowly progressing replication forks interfere with timely and error-free completion of the S phase. On the other hand, mitotic errors that result in chromosome mis-segregation are the cause of numerical chromosome instability (n-CIN) and aneuploidy. In this review, we will discuss recent evidence showing that these two forms of chromosomal instability can be mechanistically interlinked. We first summarize how replication stress causes structural and numerical CIN, focusing on mechanisms such as mitotic rescue of replication stress (MRRS) and centriole disengagement, which prevent or contribute to specific types of structural chromosome aberrations and segregation errors. We describe the main outcomes of segregation errors and how micronucleation and aneuploidy can be the key stimuli promoting inflammation, senescence, or chromothripsis. At the end, we discuss how CIN can reduce cellular fitness and may behave as an anticancer barrier in noncancerous cells or precancerous lesions, whereas it fuels genomic instability in the context of cancer, and how our current knowledge may be exploited for developing cancer therapies.

show abstract

Section: Mechanisms Protecting Against Replication Stress and Under-rmentioning

confidence: 99%

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Wilhelm

Said

Naim

2020

Genes

Self Cite

105

View full text Add to dashboard Cite

show abstract

“…For RNAi, cells were plated in 6-well dishes one day before transfection [ 17 ] and the siRNA transfection was performed as previously described [ 16 ]. Briefly, cells were transfected with a specific siRNA targeting CENP-E (siCENP-E: 5′-AAC GAAGAGUUACUUGGUGCCtt-3′) at a final concentration of 40 nM, which does not affect cell viability, as previously described [ 9 ].…”

Section: Methodsmentioning

confidence: 99%

Transcriptomic Changes Following Partial Depletion of CENP-E in Normal Human Fibroblasts

Cilluffo

Chiavetta

Bivona

et al. 2021

Genes

Self Cite

View full text Add to dashboard Cite

The centromere is a fundamental chromosome structure in which the macro-molecular kinetochore assembles and is bound by spindle microtubules, allowing the segregation of sister chromatids during mitosis. Any alterations in kinetochore assembly or functioning or kinetochore–microtubule attachments jeopardize chromosome stability, leading to aneuploidy, a common feature of cancer cells. The spindle assembly checkpoint (SAC) supervises this process, ensuring a faithful segregation of chromosomes. CENP-E is both a protein of the kinetochore and a crucial component of the SAC required for kinetochore–microtubule capture and stable attachment, as well as congression of chromosomes to the metaphase plate. As the function of CENP-E is restricted to mitosis, its haploinsufficiency has been used to study the induced cell aneuploidy; however, the gene expression profile triggered by CENP-E reduction in normal cells has never been explored. To fill this gap, here we investigated whether a gene network exists that is associated with an siRNA-induced 50% reduction in CENP-E and consequent aneuploidy. Gene expression microarray analyses were performed at early and late timepoints after transfection. Initially, cell cycle regulation and stress response pathways were downregulated, while afterwards pathways involved in epithelial–mesenchymal transition, hypoxia and xenobiotic metabolism were altered. Collectively, our results suggest that CENP-E reduction triggers a gene expression program that recapitulates some features of tumor cells.

show abstract

“…Some of the key proteins involved in these pathways are summarized in Table 1. Interestingly, deficiency in some of these proteins such as FANCD2, ATR, RNase H1, and Dicer, have been linked to CFSs fragility (Casper et al, 2002;Madireddy et al, 2016;Di Marco et al, 2017;Fragkos et al, 2019), indicating cells employ these pathways to counteract transcription induced obstacles or RS to maintain CFS stability. Of note, most of these pathways seem to largely operate in S phase of the cell cycle.…”

Section: Pathways In Dealing With Transcription Associated Rs At Cfssmentioning

confidence: 99%

Transcription-Replication Collisions and Chromosome Fragility

Lan

et al. 2021

Front. Genet.

View full text Add to dashboard Cite

Accurate replication of the entire genome is critical for cell division and propagation. Certain regions in the genome, such as fragile sites (common fragile sites, rare fragile sites, early replicating fragile sites), rDNA and telomeres, are intrinsically difficult to replicate, especially in the presence of replication stress caused by, for example, oncogene activation during tumor development. Therefore, these regions are particularly prone to deletions and chromosome rearrangements during tumorigenesis, rendering chromosome fragility. Although, the mechanism underlying their “difficult-to-replicate” nature and genomic instability is still not fully understood, accumulating evidence suggests transcription might be a major source of endogenous replication stress (RS) leading to chromosome fragility. Here, we provide an updated overview of how transcription affects chromosome fragility. Furthermore, we will use the well characterized common fragile sites (CFSs) as a model to discuss pathways involved in offsetting transcription-induced RS at these loci with a focus on the recently discovered atypical DNA synthesis repair pathway Mitotic DNA Synthesis (MiDAS).

show abstract

Dicer prevents genome instability in response to replication stress

Cited by 14 publications

References 79 publications

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Transcriptomic Changes Following Partial Depletion of CENP-E in Normal Human Fibroblasts

Transcription-Replication Collisions and Chromosome Fragility

Contact Info

Product

Resources

About