Redeployment of Myc and E2f1–3 drives Rb -deficient cell cycles

Robust mechanisms to control cell proliferation have evolved to maintain the integrity of organ architecture. Here, we investigated how two critical proliferative pathways, Myc and E2f, are integrated to control cell cycles in normal and Rb -deficient cells using a murine intestinal model. We show that Myc and E2f1–3 have little impact on normal G 1 –S transitions. Instead, they synergistically control an S–G 2 transcriptional program required for normal cell divisions and maintaining crypt–villus integrity. Surprisingly, Rb deficiency results in the Myc-dependent accumulation of E2f3 protein and chromatin repositioning of both Myc and E2f3, leading to the ‘super activation’ of a G 1 –S transcriptional program, ectopic S phase entry and rampant cell proliferation. These findings reveal that Rb -deficient cells hijack and redeploy Myc and E2f3 from an S–G 2 program essential for normal cell cycles to a G 1 –S program that re-engages ectopic cell cycles, exposing an unanticipated addiction of Rb -null cells on Myc.