Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes

Helmrich, Anne; Ballarino, Monica; Tora, Làszlò

doi:10.1016/j.molcel.2011.10.013

Cited by 484 publications

(558 citation statements)

References 60 publications

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“…4). The transcription of large genes can lead to FS expression as a result of a collision between transcription and replication 25 , and oncogene overexpression can lead to transcriptional changes. Hence, we performed Real-time PCR on several very large genes (4600 kb) located within chromosomal bands harbouring FSs that differ in their expression between cyclin E and aphidicolin-treated cells.…”

Section: Resultsmentioning

confidence: 99%

Oncogenes create a unique landscape of fragile sites

et al. 2015

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Recurrent genomic instability in cancer is attributed to positive selection and/or the sensitivity of specific genomic regions to breakage. Among these regions are fragile sites (FSs), genomic regions sensitive to replication stress conditions induced by the DNA polymerase inhibitor aphidicolin. However, the basis for the majority of cancer genomic instability hotspots remains unclear. Aberrant oncogene expression induces replication stress, leading to DNA breaks and genomic instability. Here we map the cytogenetic locations of oncogene-induced FSs and show that in the same cells, each oncogene creates a unique fragility landscape that only partially overlaps with aphidicolin-induced FSs. Oncogene-induced FSs colocalize with cancer breakpoints and large genes, similar to aphidicolin-induced FSs. The observed plasticity in the fragility landscape of the same cell type following oncogene expression highlights an additional level of complexity in the molecular basis for recurrent fragility in cancer.

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Section: Resultsmentioning

confidence: 99%

Oncogenes create a unique landscape of fragile sites

et al. 2015

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“…Replication fork stalling near Nf1 has been noted at a 5-kb isochore transition zone conserved between human and mouse, separating early and late replicating chromatin (Schmegner et al 2005). Furthermore, collisions between replication and transcription complexes cause instability at fragile sites in the longest human genes (Helmrich et al 2011). In the case of Chaos3 cancers, there may be a predisposition for replication fork stalling at particular genomic regions that are problematic for the destabilized Chaos3 helicase (Chuang et al 2012), coupled with selective growth advantage conferred to cells by such mutations.…”

Section: Discussionmentioning

confidence: 99%

Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver

Wallace¹,

Pfefferle

Shen³

et al. 2012

Genetics

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Identifying genomic alterations driving breast cancer is complicated by tumor diversity and genetic heterogeneity. Relevant mouse models are powerful for untangling this problem because such heterogeneity can be controlled. Inbred Chaos3 mice exhibit high levels of genomic instability leading to mammary tumors that have tumor gene expression profiles closely resembling mature human mammary luminal cell signatures. We genomically characterized mammary adenocarcinomas from these mice to identify cancer-causing genomic events that overlap common alterations in human breast cancer. Chaos3 tumors underwent recurrent copy number alterations (CNAs), particularly deletion of the RAS inhibitor Neurofibromin 1 (Nf1) in nearly all cases. These overlap with human CNAs including NF1, which is deleted or mutated in 27.7% of all breast carcinomas. Chaos3 mammary tumor cells exhibit RAS hyperactivation and increased sensitivity to RAS pathway inhibitors. These results indicate that spontaneous NF1 loss can drive breast cancer. This should be informative for treatment of the significant fraction of patients whose tumors bear NF1 mutations.

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“…Changes in origin density could also interfere with the spatial coordination of replication initiation and transcription, which may increase collisions between replication and transcription complexes, thereby causing DNA damage and genomic instability. 11,[22][23][24][25] As it is downstream of major oncogenic signaling pathways, Cyclin E seems likely to be an important mediator of oncogene effects on replication. Cyclin E is tumor promoting itself if overexpressed in mice and is found overexpressed in a variety of cancers, which correlates with low disease-free survival.…”

Section: Introductionmentioning

confidence: 99%

Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress

et al. 2012

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It has become increasingly clear that oncogenes not only provide aberrant growth signals to cells but also cause DNA damage at replication forks (replication stress), which activate the ataxia telangiectasia mutated (ATM)/p53-dependent tumor barrier. Here we studied underlying mechanisms of oncogene-induced replication stress in cells overexpressing the oncogene Cyclin E. Cyclin E overexpression is associated with increased firing of replication origins, impaired replication fork progression and DNA damage that activates RAD51-mediated recombination. By inhibiting replication initiation factors, we show that Cyclin E-induced replication slowing and DNA damage is a consequence of excessive origin firing. A significant amount of Cyclin E-induced replication slowing is due to interference between replication and transcription, which also underlies the activation of homologous recombination. Our data suggest that Cyclin E-induced replication stress is caused by deregulation of replication initiation and increased interference between replication and transcription, which results in impaired replication fork progression and DNA damage triggering the tumor barrier or cancer-promoting mutations.Oncogene ( Keywords: Cyclin E; replication fork; origin firing; DNA damage; homologous recombination INTRODUCTION Faithful replication of the genome is essential to maintain genomic stability and prevent cancer-promoting mutations. If the progression of replication forks is impaired, this can lead to replicationassociated DNA damage, also known as replication stress. It is now recognized that replication stress induced by oncogenes is an important factor that underlies the activation of the ataxia telangiectasia mutated (ATM)-and p53-mediated tumor barriers of senescence and apoptosis. [1][2][3][4][5][6][7] There is currently no coherent model to explain how oncogenes induce replication stress and DNA damage. Oncogenes of the growth factor signaling pathways generally activate cell proliferation by deregulating the transition from G1 to S phase of the cell cycle.8 Deregulated S-phase entry leading to aberrant DNA replication is therefore likely a principal mechanism of oncogene-induced replication stress. It has been reported that overexpression of the oncogenes HPV-16 E6/E7 and Cyclin E leads to S-phase entry in the presence of insufficient nucleotide pools, leading to impaired DNA replication fork progression and DNA damage.9 However, the underlying mechanism for the nucleotide depletion observed in the presence of oncogenes is not clear, and not all oncogenes that deregulate S-phase entry induce DNA damage. 10 The mechanisms of aberrant DNA replication and oncogene-induced replication stress therefore deserve further scrutiny.During a normal cell cycle, not only entry into S phase but also the timing of DNA replication initiation during S phase is carefully regulated by cell cycle and checkpoint signaling pathways.

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Collisions between Replication and Transcription Complexes Cause Common Fragile Site Instability at the Longest Human Genes

Cited by 484 publications

References 60 publications

Oncogenes create a unique landscape of fragile sites

Oncogenes create a unique landscape of fragile sites

Comparative Oncogenomics Implicates the Neurofibromin 1 Gene (NF1) as a Breast Cancer Driver

Increased replication initiation and conflicts with transcription underlie Cyclin E-induced replication stress

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