scholarly journals DNA-Replikationsstress, Mitose und genomische Instabilität

BIOspektrum ◽  
2021 ◽  
Vol 27 (1) ◽  
pp. 10-13
Author(s):  
Alicia Konrath ◽  
Ann-Kathrin Schmidt ◽  
Holger Bastians
Keyword(s):  
Dna Replication ◽  
Tumor Progression ◽  
Chromosome Aberrations ◽  
Chromosomal Instability ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Functional Link ◽  
Structural Chromosome ◽  
Genomische Instabilität

AbstractChromosomal instability (CIN) is a hallmark of cancer and contributes to tumorigenesis and tumor progression. While structural CIN (S-CIN) leads to structural chromosome aberrations, whole chromosome instability (W-CIN) is defined by perpetual gains or losses of chromosomes during mitosis causing aneuploidy. Mitotic defects, but also abnormal DNA replication (replication stress) can lead to W-CIN. However, the functional link between replication stress, mitosis and aneuploidy is little understood.

scholarly journals DNA Replication Stress and Chromosomal Instability: Dangerous Liaisons

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 642
Author(s):  
Therese Wilhelm ◽  
Maha Said ◽  
Valeria Naim
Keyword(s):  
Chromosome Aberrations ◽  
Chromosomal Instability ◽  
Current Knowledge ◽  
Precancerous Lesions ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Cancer Therapies ◽  
Age Related ◽  
Structural Chromosome ◽  
Dna Replication Stress

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.

scholarly journals Dormant replication origin firing links replication stress to whole chromosomal instability in human cancer

2021 ◽  
Author(s):  
Ann-Kathrin Schmidt ◽  
Nicolas Boehly ◽  
Xiaoxiao Zhang ◽  
Benjamin O. Slusarenko ◽  
Magdalena Hennecke ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Chromosomal Instability ◽  
Replication Origin ◽  
Human Cancer ◽  
Chromosome Instability ◽  
Replication Stress ◽  
S Phase ◽  
Origin Firing ◽  
Human Cancer Cells ◽  
Chromosome Missegregation

Chromosomal instability (CIN) is a hallmark of cancer and comprises structural CIN (S-CIN) and whole chromosome instability (W-CIN). Replication stress (RS), a condition of slowed or stalled DNA replication during S phase, has been linked to S-CIN, whereas defects in mitosis leading to chromosome missegregation and aneuploidy can account for W-CIN. It is well established that RS can activate additional replication origin firing that is considered as a rescue mechanism to suppress chromosomal instability in the presence of RS. In contrast, we show here that an increase in replication origin firing during S phase can contribute to W-CIN in human cancer cells. Increased origin firing can be specifically triggered by overexpression of origin firing genes including GINS1 and CDC45, whose elevated expression significantly correlates with W-CIN in human cancer specimens. Moreover, endogenous mild RS present in cancer cells characterized by W-CIN or modulation of the origin firing regulating ATR-CDK1-RIF1 axis induces dormant origin firing, which is sufficient to trigger chromosome missegregation and W-CIN. Importantly, chromosome missegregation upon increased dormant origin firing is mediated by increased microtubule growth rates leading to the generation of lagging chromosomes in mitosis, a condition prevalent in chromosomally unstable cancer cells. Thus, our study identified increased or dormant replication origin firing as a hitherto unrecognized, but cancer-relevant trigger for chromosomal instability.

scholarly journals Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 3056
Author(s):  
Sebastián Omar Siri ◽  
Julieta Martino ◽  
Vanesa Gottifredi
Keyword(s):  
Cancer Treatment ◽  
Cell Survival ◽  
Therapeutic Target ◽  
Chromosomal Instability ◽  
Structural Changes ◽  
Chromosome Instability ◽  
Chromosome Abnormalities ◽  
Cellular Mechanisms ◽  
Genomic Changes ◽  
Structural Chromosome

Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.

scholarly journals Replication Timing and Transcription Identifies a Novel Fragility Signature Under Replication Stress

2019 ◽  
Author(s):  
Dan Sarni ◽  
Takayo Sasaki ◽  
Karin Miron ◽  
Michal Irony Tur-Sinai ◽  
Juan Carlos Rivera-Mulia ◽  
...  
Keyword(s):  
Dna Replication ◽  
Chromosomal Instability ◽  
Temporal Order ◽  
Replication Timing ◽  
Replication Stress ◽  
Fragile Sites ◽  
Precise Mapping ◽  
Chromosomal Fragility ◽  
Transcriptional Changes ◽  
Large Genes

AbstractCommon fragile sties (CFSs) are regions susceptible to replication stress and are hotspots for chromosomal instability in cancer. Several features characterizing CFSs have been associated with their instability, however, these features are prevalent across the genome and do not account for all known CFSs. Therefore, the molecular mechanism underlying CFS instability remains unclear. Here, we explored the transcriptional profile and temporal order of DNA replication (replication timing, RT) of cells under replication stress conditions. We show that the RT of only a small portion of the genome is affected by replication stress, and that CFSs are enriched for delayed RT. We identified a signature for chromosomal fragility, comprised of replication stress-induced delay in RT of early/mid S-phase replicating regions within actively transcribed large genes. This fragility signature enabled precise mapping of the core fragility region. Furthermore, the signature enabled the identification of novel fragile sites that were not detected cytogenetically, highlighting the improved sensitivity of our approach for identifying fragile sites. Altogether, this study reveals a link between altered DNA replication and transcription of large genes underlying the mechanism of CFS expression. Thus, investigating the RT and transcriptional changes in cancer may contribute to the understanding of mechanisms promoting genomic instability in cancer.

scholarly journals Emerging functions of Fanconi anemia genes in replication fork protection pathways

2020 ◽  
Vol 29 (R2) ◽  
pp. R158-R164 ◽  
Author(s):  
Arun Mouli Kolinjivadi ◽  
Wayne Crismani ◽  
Joanne Ngeow
Keyword(s):  
Dna Replication ◽  
Fanconi Anemia ◽  
Replication Fork ◽  
Genome Stability ◽  
Chromosome Instability ◽  
Replication Stress ◽  
Short Review ◽  
Gene Products ◽  
Dna Double Strand Breaks ◽  
Variants Of Unknown Significance

Abstract Germline mutations in Fanconi anemia (FA) genes predispose to chromosome instability syndromes, such as FA and cancers. FA gene products have traditionally been studied for their role in interstrand cross link (ICL) repair. A fraction of FA gene products are classical homologous recombination (HR) factors that are involved in repairing DNA double-strand breaks (DSBs) in an error-free manner. Emerging evidence suggests that, independent of ICL and HR repair, FA genes protect DNA replication forks in the presence of replication stress. Therefore, understanding the precise function of FA genes and their role in promoting genome stability in response to DNA replication stress is crucial for diagnosing FA and FA-associated cancers. Moreover, molecular understanding of the FA pathway will greatly help to establish proper functional assays for variants of unknown significance (VUS), often encountered in clinics. In this short review, we discuss the recently uncovered molecular details of FA genes in replication fork protection pathways. Finally, we examine how novel FA variants predispose to FA and cancer, due to defective replication fork protection activity.

scholarly journals PARI Regulates Stalled Replication Fork Processing To Maintain Genome Stability upon Replication Stress in Mice

2017 ◽  
Vol 37 (23) ◽  
Author(s):  
Ayako L. Mochizuki ◽  
Ami Katanaya ◽  
Eri Hayashi ◽  
Mihoko Hosokawa ◽  
Emiko Moribe ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Replication ◽  
Genome Stability ◽  
Ex Vivo ◽  
Chromosome Instability ◽  
Embryonic Stem ◽  
Replication Stress ◽  
Genotoxic Stress ◽  
Origin Firing

ABSTRACT DNA replication is frequently perturbed by intrinsic, as well as extrinsic, genotoxic stress. At damaged forks, DNA replication and repair activities require proper coordination to maintain genome integrity. We show here that PARI antirecombinase plays an essential role in modulating the initial response to replication stress in mice. PARI is functionally dormant at replisomes during normal replication, but upon replication stress, it enhances nascent-strand shortening that is regulated by RAD51 and MRE11. PARI then promotes double-strand break induction, followed by new origin firing instead of replication restart. Such PARI function is apparently obstructive to replication but is nonetheless physiologically required for chromosome stability in vivo and ex vivo. Of note, Pari-deficient embryonic stem cells exhibit spontaneous chromosome instability, which is attenuated by differentiation induction, suggesting that pluripotent stem cells have a preferential requirement for PARI that acts against endogenous replication stress. PARI is a latent modulator of stalled fork processing, which is required for stable genome inheritance under both endogenous and exogenous replication stress in mice.

Induction of APOBEC3 exacerbates DNA replication stress and chromosomal instability in early breast and lung cancer evolution

2021 ◽  
pp. candisc.0725.2020
Author(s):  
Subramanian Venkatesan ◽  
Mihaela Angelova ◽  
Clare Puttick ◽  
Haoran Zhai ◽  
Deborah R Caswell ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Replication ◽  
Chromosomal Instability ◽  
Replication Stress ◽  
Cancer Evolution ◽  
Dna Replication Stress

scholarly journals DNA Replication Stress Generates Distinctive Landscapes of DNA Copy Number Alterations and Chromosome Scale Losses

2019 ◽  
Author(s):  
Alice Mazzagatti ◽  
Nadeem Shaikh ◽  
Bjorn Bakker ◽  
Diana Carolina Johanna Spierings ◽  
René Wardenaar ◽  
...  
Keyword(s):  
Dna Replication ◽  
Single Cell ◽  
Copy Number ◽  
Chromosomal Instability ◽  
Replication Stress ◽  
Fragile Sites ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Dna Copy Number Alterations ◽  
The Impact

AbstractBackgroundWe previously showed that a major driver of cancer chromosomal instability (CIN) is replication stress, the slowing or stalling of DNA replication. However, the precise drivers of replication stress in cancer and the mechanisms by which these cause CIN and influence tumour evolution remain unclear. Common fragile sites are well-known genomic locations of breakage after aphidicolin-induced replication stress, but their precise causes of fragility are debated, and additional genomic consequences of replication stress are not fully explored.ResultsUsing single cell sequencing we detected DNA copy number alterations (CNAs) caused by one cell cycle under replication stress in diploid non-transformed cells. Aphidicolin-induced replication stress caused multiple types of CNAs associated with different genomic regions and features. Coupling cell type-specific analysis of CNAs to gene expression and single cell replication timing analyses allowed us to pinpoint the causative large genes of the most recurrent chromosome-scale CNAs. In RPE1 cells these were largely confined to three sites on chromosomes 1, 2 and 7 and generated acentric lagging chromatin and micronuclei containing these chromosomes. Different replicative stresses generated distinct profiles of CNAs providing the potential to interpret specific replication stress mechanisms from cancer cells.ConclusionsChromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm-scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution trajectories. Single cell CNA analysis thus reveals new insights into the impact of replication stress on the genome and provides a platform to further dissect molecular mechanisms involved in the replication stress response and to gain insights into how replication stress fuels chromosomal instability in cancer.

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