Biology subjects

Bertoli, C.

Publications and source records attributed to Bertoli, C..

4 recordsLinked to original sources

bioRxiv2022

Oncogenic c-Myc activity increases tolerance to proteotoxic and genotoxic stress through regulation of HSF1

Oncogenes, such as c-Myc, enhance growth and proliferative signaling to promote continuous cell cycle divisions, the hallmark of cancer. The inadvertent consequence of this is an increase in cellular stresses. However, whether and how oncogenes can directly contribute to cellular stress tolerance, and how much cancer cells rely on these mechanisms for survival, remains poorly understood. Here we show that c-Mycdependent proteotoxic stress contributes to the generation of genotoxic stress. We reveal an important role for the transcription factor Heat Shock Factor 1 (HSF1) in the tolerance to both these c-Myc-induced stresses. c-Myc upregulates HSF1 directly, by activating its expression, and indirectly, via c-Mycdependent proteotoxic stress activation. In addition to relieving c-Myc-induced proteotoxic and genotoxic stress, HSF1 also enables DNA damage response signalling through{gamma} H2AX. Consequently, acute depletion of HSF1 significantly increases c-Myc-driven genome instability and decreases cell viability. Our results establish that c-Myc-dependent regulation of HSF1 ensures that proteotoxic and genotoxic stress, resulting from c-Myc-induced enhanced growth and proliferation, are compatible with cell survival.

cancer biology↗

bioRxiv2021

Active growth signalling promotes cancer cell sensitivity to the CDK7 inhibitor ICEC0942

CDK7 has a central role in promoting cellular proliferation, through the activation of the mitotic CDKs, and by driving global gene expression, through targeting RNA polymerase II. Several recently developed CDK7 inhibitors (CDK7i) have been shown to be non-toxic and to limit tumour growth for a number of cancer cell types and are now in Phase I/II clinical trials. However, the mechanisms underlying the sensitivity of particular cancer cells to CDK7 inhibition remain largely unknown. To improve the outcome of individual patients and increase the chances of successful CDK7i approval, we assessed which fundamental cellular processes determine sensitivity to CDK7 inhibition, using the highly specific CDK7 inhibitor ICEC0942. Our data shows that selective CDK7 inhibition acutely arrests cells in the G1 phase of the cell cycle, which over time leads to senescence. Through a genome-wide CRISPR knock-out chemogenetic screen we identified active mTOR (mammalian target of rapamycin) signalling, as an important determinant of ICEC0942-induced senescence and show that a cancer-associated mutation that promotes cell growth can increase sensitivity to ICEC0942. Our work indicates that cellular growth is an important predictive marker for sensitivity to CDK7i.

cancer biology↗

bioRxiv2021

Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy

Oncogene-induced replication stress is a major driver of genomic instability in cancer cells, with a central role in both cancer initiation and progression (1). Despite its critical role in cancer development, the mechanisms that lay at the basis of oncogene-induced replication stress remains poorly understood. Here, we investigate the mechanism of c-Myc-induced replication stress. Our data shows that c-Myc induces replication stress by increasing the amount of cohesins bound to chromatin in the G1 phase of the cell cycle. This is independent of previously suggested mechanisms involving deregulation of replication initiation and transcriptional interference. Restoring the amount of chromatin-bound cohesins to control levels, or preventing the accumulation of cohesins at CTCF sites, in cells experiencing oncogenic c-Myc activity prevents replication stress. Increased cohesins chromatin occupancy correlates with a c-Myc-dependent increase in the levels of the cohesion loader Mau2. Preventing c-Myc-induced increase in Mau2 reduces oncogene-induced replication stress. Together our data support a novel mechanism for oncogene-induced replication stress. Since c-Myc activation is a crucial event in many human cancers (2), identifying the mechanisms through which this oncogene promotes replication stress provides critical insights into cancer biology.

cancer biology↗

bioRxiv2021

Vaccinia Virus Arrests and Shifts the Cell Cycle

Modulation of the host cell cycle is a common strategy used by viruses to create a pro-replicative environment. To facilitate viral genome replication, vaccinia virus (VACV) has been reported to alter cell cycle regulation and trigger the host cell DNA damage response. However, the cellular factors and viral effectors that mediate these changes remain unknown. Here, we set out to investigate the effect of VACV infection on cell proliferation and host cell cycle progression. Using a subset of VACV mutants we characterize the stage of infection required for inhibition of cell proliferation and define the viral effectors required to dysregulate the host cell cycle. Consistent with previous studies, we show that VACV inhibits, and subsequently shifts the host cell cycle. We demonstrate that these two phenomena are independent of one another, with viral early genes being responsible for cell cycle inhibition, and post-replicative viral gene(s) responsible for the cell cycle shift. Extending previous findings, we show that the viral kinase F10 is required to activate the DNA damage checkpoint and that the viral B1/B12 (pseudo) kinases mediate degradation of checkpoint effectors p53 and p21 during infection. We conclude that VACV modulates host cell proliferation and host cell cycle progression through temporal expression of multiple VACV effector proteins.

microbiology↗