Myc induced replicative stress response: How to cope with it and exploit it

Rohban, Sara; Campaner, Stefano

doi:10.1016/j.bbagrm.2014.04.008

Cited by 65 publications

(74 citation statements)

References 139 publications

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“…It is a potent oncoprotein that is highly expressed in Burkitt lymphomas. High levels of MYC protein induce cellular growth, cell cycle entry and cell proliferation, but, as a consequence, also cause replication stress (Rohban and Campaner, 2015). Induced overexpression of MYC increases the fraction of S-phase cells and accelerates S-phase progression probably by initiating premature origin firing.…”

Section: The Limitations Of the In Vitro B Cell Infection Modelmentioning

confidence: 99%

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Pich

Mrozek-Górska

Bouvet

et al. 2019

Preprint

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Epstein-Barr virus (EBV) infects and activates resting human B-lymphocytes, reprograms them, induces their proliferation, and establishes a latent infection in them. In established EBV-infected cell lines many viral latent genes are expressed. Their roles in supporting the continuous proliferation of EBV-infected B cells in vitro are known, but their functions in the early, pre-latent phase of infection have not been investigated systematically. In studies during the first eight days of infection using derivatives of EBV with mutations in single genes of EBVs we found only EBNA2 to be essential for activating naïve human B-lymphocytes, inducing their growth in cell volume, driving them into rapid cell divisions, and preventing cell death in a subset of infected cells. EBNA-LP, LMP2A and the viral microRNAs have supportive, auxiliary functions, but mutants of LMP1, EBNA3A, EBNA3C, and the noncoding EBER RNAs had no discernable phenotype compared with wild-type EBV. B cells infected with a double mutant of EBNA3A and 3C had an unexpected proliferative advantage and did not regulate the DNA damage response (DDR) of the infected host cell in the pre-latent phase. Even EBNA1 which has very critical longterm functions in maintaining and replicating the viral genomic DNA in established cell lines, was dispensable for the early activation of infected cells. Our findings document that the virus dose is a critical parameter and indicate that EBNA2 governs the infected cells initially and implements a strictly controlled temporal program independent of other viral latent genes. It thus appears that EBNA2 is sufficient to control all requirements for clonal cellular expansion and to reprogram human B-lymphocytes from energetically quiescent to activated cells. Author summaryThe preferred target of Epstein-Barr virus (EBV) are human resting B-lymphocytes. We found that their infection induces a well-coordinated, time-driven program that starts with a substantial 3 increase in cell volume followed by cellular DNA synthesis after three days and subsequent rapid rounds of cell divisions on the next day accompanied by some DNA replication stress (DRS). Two to three days later the cells decelerate and turn into stably proliferating lymphoblast cell lines. With the aid of 16 different recombinant EBV strains we investigated the individual contributions of EBV's multiple latent genes during early B-cell infection and found that many do not exert a detectable phenotype or contribute little to EBV's pre-latent phase. The exception is EBNA2 that is essential in governing all aspects of B-cell reprogramming. EBV relies on EBNA2 to turn the infected B-lymphocytes into proliferating lymphoblasts preparing the infected host cell for the ensuing stable, latent phase of viral infection. In the early steps of B-cell reprogramming viral latent genes other than EBNA2 are dispensable but some, EBNA-LP for example, support the viral program and presumably stabilize the infected cells once viral latency is established.

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Section: The Limitations Of the In Vitro B Cell Infection Modelmentioning

confidence: 99%

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Pich

Mrozek-Górska

Bouvet

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Additionally, a given oncogene can lead to stress through a number of different mechanisms occurring simultaneously. For example, a recent review of the contribution of c-myc to replication stress [50] suggested two coexisting mechanisms for fork stalling induction: over usage of origins resulting in depletion of resources and increased interference between transcription and replication.…”

Section: Replication Stressmentioning

confidence: 99%

Perturbations in the Replication Program Contribute to Genomic Instability in Cancer

Blumenfeld

Ben-Zimra

Simon

2017

IJMS

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Cancer and genomic instability are highly impacted by the deoxyribonucleic acid (DNA) replication program. Inaccuracies in DNA replication lead to the increased acquisition of mutations and structural variations. These inaccuracies mainly stem from loss of DNA fidelity due to replication stress or due to aberrations in the temporal organization of the replication process. Here we review the mechanisms and impact of these major sources of error to the replication program.

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“…Oncogenes can be a source of genomic instability, and some of them act through replication stress [27, 28]. Having previously demonstrated that abnormal Spi1 expression triggers replicative stress [13], we aimed to identify its underlying mechanism(s) of action.…”

Section: Discussionmentioning

confidence: 99%

The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia

et al. 2017

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Oncogenes trigger replicative stress that can lead to genetic instability, which participates in cancer progression. Thus, determining how cells cope with replicative stress can help our understanding of oncogenesis and lead to the identification of new antitumor treatment targets. We previously showed that constitutive overexpression of the oncogenic transcription factor Spi1/PU.1 leads to pre-leukemic cells that have a shortened S phase duration with an increased replication fork speed and increased mutability in the absence of DNA breaks. Here, we demonstrate that the S phase checkpoint protein CHK1 is maintained in a low phosphorylation state in Spi1/PU.1-overexpressing cells and provide evidence that this is not due to negative control of its primary kinase ATR. Notably, we found that the expression of the CHK1 phosphatase PP1α is increased in Spi1/PU.1-overexpressing cells. By exogenously modulating its activity, we demonstrate that PP1α is required to maintain CHK1 in a dephosphorylated state and, more importantly, that it is responsible for the accelerated replication fork progression in Spi1/PU.1-overexpressing cells. These results identify a novel pathway by which an oncogene influences replication in the absence of DNA damage.

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Myc induced replicative stress response: How to cope with it and exploit it

Cited by 65 publications

References 139 publications

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

The first days in the life of naïve human B-lymphocytes infected with Epstein-Barr virus

Perturbations in the Replication Program Contribute to Genomic Instability in Cancer

The Spi1/PU.1 transcription factor accelerates replication fork progression by increasing PP1 phosphatase in leukemia

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