Stalled Fork Rescue via Dormant Replication Origins in Unchallenged S Phase Promotes Proper Chromosome Segregation and Tumor Suppression

Kawabata, Tsuyoshi; Luebben, Spencer W.; Yamaguchi, Satoru; Ilves, Ivar; Matise, Ilze; Buske, Tavanna R.; Botchan, Michael R.; Shima, Naoko

doi:10.1016/j.molcel.2011.02.006

Cited by 184 publications

(283 citation statements)

References 55 publications

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“…Although Cyclin E is required to promote minichromosome maintenance complex loading during exit from quiescence in a Cdk-independent manner, 44 overexpression of Cyclin E has been observed to inhibit minichromosome maintenance complex loading. 29 As activation of dormant origins protects cells from replication stress, 42,45 this might exacerbate the effects of replication fork stalling, incomplete replication, DNA damage and genomic instability (see model in Figure 6c). Incomplete replication causes DNA damage and has been linked to rearrangements at common fragile sites and chromosomal instability, the most common form of genomic instability in sporadic cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Incomplete replication causes DNA damage and has been linked to rearrangements at common fragile sites and chromosomal instability, the most common form of genomic instability in sporadic cancers. [45][46][47] Higher levels of origin firing mean that more replication forks are active simultaneously, and it appears likely that replication elongation factors such as deoxyribonucelotides (dNTPs) become limiting under these conditions. Indeed, it was recently reported that Cyclin E overexpression decreased dNTP pools, resulting in decreased replication fork progression and replication stress.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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“…One possible explanation may be related to differential DNA replication mechanics per se. Chaos3 cells have reduced Mcm2-7 mRNA and protein levels that lead to a decreased number of backup ("dormant") replication origins (Kawabata et al 2011a;Chuang et al 2012), and these two strains differ in the density of licensed origins (Kawabata et al 2011b). Backup origins are important for rescue of stalled or collapsed DNA replication forks that may otherwise lead to chromosomal aberrations (Blow et al 2011).…”

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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“…The Chaos3 mouse, bearing a missense allele (Mcm4 Chaos3 ) of the DNA replication gene Mcm4, exhibits high levels of genomic instability caused by the mutation's destabilization of the MCM2-7 replicative helicase complex (Shima et al 2007;Kawabata et al 2011;Chuang et al 2012). Most females homozygous for the Chaos3 mutation congenic in the C3HeB/FeJ strain background (C3H-Chaos3) develop spontaneous mammary tumors (MTs) with an average latency of 12 months (Shima et al 2007).…”

Section: Resultsmentioning

confidence: 99%

“…Since Chaos3 cells have chronic replication stress and GIN (Shima et al 2007;Kawabata et al 2011;Bai et al 2016), it is possible that a loss or reduction of ARID1A in a cell allows escape from DDR-mediated growth arrest or apoptosis, thus promoting carcinogenesis. Therefore, we examined the cell cycle of AB-C1 cultures.…”

Section: Resultsmentioning

confidence: 99%

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

Kartha¹,

Shen

Maskin³

et al. 2016

Genetics

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Human cancer genome studies have identified the SWI/SNF chromatin remodeling complex member ARID1A as one of the most frequently altered genes in several tumor types. Its role as an ovarian tumor suppressor has been supported in compound knockout mice. Here, we provide genetic and functional evidence that Arid1a is a bona fide mammary tumor suppressor, using the Chromosome aberrations occurring spontaneously 3 (Chaos3) mouse model of sporadic breast cancer. About 70% of mammary tumors that formed in these mice contained a spontaneous deletion removing all or part of one Arid1a allele. Restoration of Arid1a expression in a Chaos3 mammary tumor line with low Arid1a levels greatly impaired its ability to form tumors following injection into cleared mammary glands, indicating that ARID1A insufficiency is crucial for maintenance of these Trp53-proficient tumors. Transcriptome analysis of tumor cells before and after reintroduction of Arid1a expression revealed alterations in growth signaling and cell-cycle checkpoint pathways, in particular the activation of the TRP53 pathway. Consistent with the latter, Arid1a reexpression in tumor cells led to increased p21 (Cdkn1a) expression and dramatic accumulation of cells in G2 phase of the cell cycle. These results not only provide in vivo evidence for a tumor suppressive and/or maintenance role in breast cancer, but also indicate a potential opportunity for therapeutic intervention in ARID1A-deficient human breast cancer subtypes that retain one intact copy of the gene and also maintain wild-type TRP53 activity.

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Stalled Fork Rescue via Dormant Replication Origins in Unchallenged S Phase Promotes Proper Chromosome Segregation and Tumor Suppression

Cited by 184 publications

References 55 publications

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

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

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

The Chromatin Remodeling Component Arid1a Is a Suppressor of Spontaneous Mammary Tumors in Mice

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