PARP-1 as a cell cycle regulator – a new job for an old friend.
Pablo Iglesias; Irene Golán*; Marcos Seoane; Isabel Castro; Victor Arce; Jose A. Costoya, Molecular Oncology Laboratory, Departamento de Fisioloxía, Centro de Investigación en Medicina Molecular e Enfermidades Crónicas (CIMUS), Universidade de Santiago de Compostela (Spain).
Although PARP-1 has been traditionally linked to roles related to DNA repair, in recent years the number of studies discovering novel functions for this protein has steadily increased. In this study we wanted to investigate the biological roles of the interaction between PARP-1 and E2F-1, mainly in scenarios in which the transcription factor E2F-1 is of critical importance such as embryonic development and oncogenesis.
In this regard, we have found that the treatment either with an enzymatic inhibitor of PARP-1 activity or a specific inhibitor of PARP-1 protein-protein interactions significantly reduces the transcriptional activity of E2F-1 as well as the proliferative rate of treated cells. The role of PARP-1 as a co-activator of E2F-1 is not just restricted to cell cycle but it also affects complex and lengthy processes such as embryogenesis or oncogenesis. We also observed that phenotype observed in Parp-1-/- Rb-/- embryos closely resembles that of E2f-1-/- Rb-/- mice, in which the severity of histological malformations caused by the absence of retinoblastoma is significantly reduced. In the same way, we also found that the deletion or inhibition of PARP-1 in an animal model of gliomagenesis helps the cell to block oncogenic stimuli by reactivating critical signalling pathways involved in oncogene-induced senescence that entail a reduction of their proliferative rate.
In summary, the understanding of biological implications of the interaction between PARP-1 and E2F-1 could serve as the foundation of novel strategies in developing novel molecules able to disrupt this protein-protein interaction.