Model for Pc-G and MLL1 proteins in regulation of cellular senescence at the <i>INK4a/ARF</i> locus.

<p>(A) In young proliferating cells, the PRC2 complex is bound at RD and at the <i>INK4a/ARF</i> locus and maintains the levels of H3K27me3. This allows the association of M33 and BMI1-containing PRC1 complex and repression of the INK4a/ARF genes. (B) In senescent or Polycomb mutant cells binding of EZH2 is lost, leading to the disruption of the PRC2 complex, the loss of H3K27me3 and to the recruitment of the MLL1 protein. We propose a model in which Polycomb/MLL1 and JMJD3 epigenetic modifications at the RD element impact the replication timing and the expression of the locus. Moreover, in senescent cells BMI1 binding is specifically lost at the RD element.