RUNX2 is a member of the RUNX family of transcription factors, also containing the RUNX1 and RUNX3 proteins. These factors control the expression of genes essential for proper development in many cell lineages. RUNX2 plays a crucial role in the proliferation and differentiation of osteoblasts, required for bone formation. The cellular level of RUNX2 oscillates in a cell phase-specific manner, reaching a maximum at G2/M in some cells and overexpression of RUNX2 in osteoblasts blocked G1 to S phase progression. Recent studies have shown that RUNX2 may interact with p53 and change the activity of a histone deacetylase. Moreover, RUNX2 may act as an oncogene in cancer transformation, inevitably associated with genomic instability evoked by increased occurrence of DNA damage. We showed that some RUNX2 modifiers changed the sensitivity of differentiating preosteoblasts to DNA damage induced by oxidative stress. All these data suggest the involvement of RUNX2 in cellular DNA damage response (DDR), which is particularly important in osteogenesis as the process of osteoblast differentiation is associated with increasing oxidative stress. However, the mechanism underlying DDR involvement of RUNX2 is unknown. The basic question, whether RUNX2 plays a positive or destructive role in DDR in differentiating cells is still open.