UNRAVELLING THE MOLECULAR MECHANISMS UNDERLYING ONCOGENE¿INDUCED DNA DAMAGE

Activation of oncogenes in normal cells induces DNA damage accumulation and evokes a DNA damage response (DDR) that has been proposed to behave as a barrier against malignant transformation by inducing either apoptosis or cellular senescence, and therefore avoiding the clonal propagation of the transformed phenotype. Two main mechanisms have been proposed to explain the role of oncogenes in inducing DNA damage: replication stress and oxidative stress. However, further investigations are needed to fully decipher the direct mechanistic link between oncogene activation and DNA damage accumulation. To investigate the molecular mechanisms underlying PML-RARᬬ–induced DNA damage, we localised on a genome-wide scale the DNA lesions induced by the oncofusion protein by performing ChIP-sequencing analyses of γH2AX DNA damage marker. Moreover, to understand the nature of PML-RARα−induced DNA damage, it was compared to the DNA damage induced by irradiation or by the endonuclease activity of a restriction enzyme. We found that PML-RARα induces site-specific γH2AX accumulation at its binding sites, where it deregulates the expression of its target genes. Indeed, PML-RARα direct targets were associated with the largest and most intense γH2AX domains, as a consequence of recurrent DNA lesions. Therefore transcription deregulation and/or its interference with replication might be responsible for DNA damage accumulation at PML-RARα binding sites.