META-CYCLE · New players in the regulation of DNA replication fork speed

Faithful eucaryotic cell division requires spatio-temporal orchestration of multiple sequential events. Among the crucial steps to providing the daughter cells with identical set of chromosomes is the DNA replication. During this phase, cells coordinate the speed of DNA synthesis with the length of the cell cycle to ensure genome integrity. To do so, growth factors and metabolic signals are integrated primarily by D-type Cyclins. Indeed. their deregulation can directly lead to some of the hallmarks of cancer by causing proliferation that is independent of normal extracellular cues. We previously demonstrated that aberrant accumulation of Cyclin D1 results in a faster cell cycle, with uncontrolled speed of DNA replication fork progression and genome instability (Maiani & Milletti et al., 2021). Despite, frequently altered in many tumors (Musgrove et al., 2011), a unifying theory that clarify how Cyclin D1 promote cancer transformation is still lacking. In the lab of Prof. Jiri Bartek, it was previously shown that PARP1 inhibition increases replication fork speed (Maya-Mendoza et al., 2018). PARP1i uncouples the leading and lagging DNA synthesis resulting in fast fork speed and genome instability. However, it is currently unknown whether the aberrant accumulation of Cyclin D1 has similar effect on DNA synthesis as PARPi. Furthermore, it is also undetermined whether aberrant levels of Cyclin D1 could trigger metabolic changes that accelerate the speed of DNA synthesis. Taking advantage of our previous observations, we aim with this proposal to: i) identify metabolic signatures that can predict dis-regulated DNA synthesis in response to cell cycle alterations; ii) define the molecular mechanism of how cyclin D1 accumulation induces accelerated fork speed; iii) identify new metabolic genes involved in the control of S phase progression and the speed of DNA synthesis by CRISPR-Cas9 screening technology; iv) suggest druggable targets that could be used in cancer therapy.