After more than 40 years of research into the tumor-suppressive roles of the p53 transcription factor, we still lack a complete picture of how it preserves genome integrity and prevents malignant disease. Multiple transcriptional targets of p53 have been tested, either alone or in combination, to explain its action, but so far it appears that the tumor suppressive function of p53 spreads across different molecular pathways. Strikingly, the ablation of intuitively crucial anti-oncogenic responses controlled by p53, such as cell cycle arrest, apoptosis and DNA repair, is not sufficient to fully recapitulate the tumor succeptibility derived from p53 loss [1].

P53 is activated in response to many different triggers, including DNA damage, the best-studied arm of the p53 response, but also in response to mitotic errors leading to delayed mitotic traverse [2]. Key-studies in the past years pointed out that delays in mitosis, that trigger the activation of the spindle assembly checkpoint (SAC), monitoring correct kinetochore to microtubule attachments, activate p53. This is potentially due to the accumulation of DNA-damage experienced in prolonged mitoses, but does not rely on it, as it can be mediated independently of the DNA-damage response (DDR) machinery involving USP28 and 53BP1-mediated stabilization of p53. As a consequence, cells with missegregated chromosomes arrest their cell cycle in the next G1 phase [3]. This helps to prevent the proliferation of cells that have missegregated their chromosomes or chromosome fragments and are characterized by numerical or structural aneuploidies [4]. Liang and colleagues report in the current issue of CDD that p53 may have a more active role in this process by facilitating the clearance of such aneuploid cells by entosis, a peculiar type of cell death based on cell-in-cell (CIC) invasion and subsequent lysosomal degradation of the entotic cell by its host [5].

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