Replication Licensing Aberrations, Replication Stress, and Genomic Instability

Petropoulos, Michalis; Tsaniras, Spyridon Champeris; Taraviras, Stavros; Lygerou, Zoi

doi:10.1016/j.tibs.2019.03.011

Cited by 87 publications

(98 citation statements)

References 105 publications

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“…Analysis of TCGA cancer specimens presenting high CDT1 and CDC6 mRNA levels revealed increased incidence of CNGs at specific genomic loci, known to contain oncogenes, while the overall amplification rate of the cancer genomes tested was also elevated. Considering that overexpression of licensing factors has been documented in several cancer types 41 and is able to potentiate malignant transformation 40,42 , these findings point to clinical relevance for re-replication induced CNGs.…”

Section: Discussionmentioning

confidence: 66%

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Aberrant replication licensing drives Copy Number Gains across species

Nathanailidou

Petropoulos

Maxouri

et al. 2020

Preprint

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Copy Number Gains (CNGs) lead to genetic heterogeneity, driving evolution and carcinogenesis. The mechanisms promoting CNG formation however remain poorly characterized. We show that abnormal expression of the replication licensing factor Cdc18 in fission yeast, which leads to genome-wide re-replication, drives the formation of CNGs at different genomic loci, promoting the acquisition of new selectable traits. Whole genome sequencing reveals Mb long, primarily extrachromosomal amplicons. Genetic analysis shows that homology-mediated repair is required to resolve re-replication intermediates into heritable CNGs. Consistently, we show that in mammalian cells overexpression of CDC6 and/or CDT1 leads to CNGs and promotes drug resistance. In human cells, multiple repair pathways are activated upon rereplication and act antagonistically, with RAD52 promoting and 53BP1 inhibiting CNG formation. In tumours, CDT1 and/or CDC6 overexpression correlates with copy number gains genome-wide. We propose re-replication as an evolutionary-conserved driver of CNGs, highlighting a link between aberrant licensing, CNGs and cancer.

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Section: Discussionmentioning

confidence: 66%

“…1d). CNGs are common in cancer 2 , while defective replication licensing has been reported in various tumours [38][39][40][41] and proposed as an initial trigger for malignant transformation 40,42 . Therefore, we 9 provide evidence for a direct link between faulty licensing regulation and CNGs in the cancer genome.…”

Section: Discussionmentioning

confidence: 99%

Aberrant replication licensing drives Copy Number Gains across species

Nathanailidou

Petropoulos

Maxouri

et al. 2020

Preprint

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“…This process is temporally restricted to a small-time window during late mitosis and early G1, by high APC and low CDK activity. High CDK activity during the S and G2 phases inhibits the re-licensing of origin before passage through mitosis [ 36 ]. Other mechanisms that are important in regulation of replication timing include the inhibition of pre-RC proteins by phosphorylation and their ubiquitin mediated degradation [ 37 ].…”

Section: Replication Stress As a Source Of Endogenous Double Stranmentioning

confidence: 99%

Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells

Mehrotra

Mittra

2020

Genes

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Genome instability is a crucial and early event associated with an increased predisposition to tumor formation. In the absence of any exogenous agent, a single human cell is subjected to about 70,000 DNA lesions each day. It has now been shown that physiological cellular processes including DNA transactions during DNA replication and transcription contribute to DNA damage and induce DNA damage responses in the cell. These processes are also influenced by the three dimensional-chromatin architecture and epigenetic regulation which are altered during the malignant transformation of cells. In this review, we have discussed recent insights about how replication stress, oncogene activation, chromatin dynamics, and the illegitimate recombination of cell-free chromatin particles deregulate cellular processes in cancer cells and contribute to their evolution. The characterization of such endogenous sources of genome instability in cancer cells can be exploited for the development of new biomarkers and more effective therapies for cancer treatment.

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“…However, in the majority of patients without BRCA mutations, PARP inhibitors are not clearly effective. In cancer cells, constitutive activation of oncogenes is a primary cause of replication stress (Gaillard, Garcia-Muse, & Aguilera, 2015; Kotsantis, Petermann, & Boulton, 2018; Petropoulos, Champeris Tsaniras, Taraviras, & Lygerou, 2019). Although it was reported that glioblastoma stem cells suffer from upregulated DNA replication stress (Carruthers et al, 2018), the level of DNA replication stress in other types of CSCs, including breast CSCs, remains unknown.…”

Section: Introductionmentioning

confidence: 99%

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells

Murayama

Takeuchi

Yamawaki

et al. 2020

Preprint

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Cancer stem-like cells (CSCs) are responsible for the drug resistance of tumors and recurrence while they experience DNA replication stress. However, the underlying mechanisms that cause DNA replication stress in CSCs and how they compensate for this stress remain unclear. Here we provide evidence that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), which is a firing (activating) factor of the DNA replication origins, to compensate for the DNA replication stress. Expression levels of MCM10 are upregulated in CSCs and maintained by c-Myc. c-Myc-dependent collisions may take place between RNA transcription and DNA replication machinery in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to the collisions to ensure replication progression. Moreover, patient-derived breast CSCs were dependent on MCM10 for their maintenance even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. In addition, MCM10 depletion decreased the growth of cancer cells but not normal cells. Therefore, MCM10 is likely to robustly compensate for DNA replication stress and facilitate genome duplication in the S-phase in cancer cells, which is more pronounced in CSCs. We provide a preclinical rationale to target the c-Myc-MCM10 axis to prevent drug resistance and recurrence.

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Replication Licensing Aberrations, Replication Stress, and Genomic Instability

Cited by 87 publications

References 105 publications

Aberrant replication licensing drives Copy Number Gains across species

Aberrant replication licensing drives Copy Number Gains across species

Origin of Genome Instability and Determinants of Mutational Landscape in Cancer Cells

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells

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