Biology subjects

Meneguello, L.

Publications and source records attributed to Meneguello, L..

3 recordsLinked to original sources

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↗

bioRxiv2019

Proteasome-mediated protein degradation resets the cell division cycle and triggers ESCRT-III-mediated cytokinesis in an archaeon

The archaeon Sulfolobus acidocaldarius is a relative of eukaryotes known to progress orderly through its cell division cycle despite lacking obvious CDK/cyclin homologues. Here, in exploring the mechanisms underpinning archaeal cell division cycle control, we show that the proteasome of S. acidocaldarius, like its eukaryotic counterpart, regulates the transition from the end of one cell division cycle to the beginning of the next. Further, we identify the archaeal ESCRT-III homologue CdvB as a key target of the proteasome, and show that state-dependent degradation of CdvB triggers archaeal cell division by allowing constriction of a CdvB1:CdvB2 ESCRT-III division ring. These findings suggest an ancient role for proteasome-mediated degradation in resetting the cell division cycle in both archaea and eukaryotes.

cell biology↗