Shortly after cell division, a robust wave of hyper-transcription reactivates the genome 1-3 . This phenomenon is particularly pronounced in pluripotent cells 4 , which necessitate rapid transcrip-tome reactivation to maintain their undifferentiated state and prevent premature differentiation. While recent work has illuminated how specific groups of genes are reactivated 4-8 , the mechanisms enabling the global, efficient and accurate post-mitotic reactivation of the genome remain unknown. Here we elucidate the direct involvement of the MYC/MAX transcription factors in the post-mitotic reactivation of pluripotent mouse embryonic stem cells. While MYC undergoes extensive phosphorylation and largely dissociates from its DNA binding sites during mitosis, we report that MAX remains bound to its targets, preferentially at promoters, and facilitates early recruitment of MYC following mitosis. Through the application of MYC/MAX heterodimerization inhibitors, we demonstrate their indispensable role in sustaining hyper-transcription in ES cells, including during the critical transition from mitosis to G1 phase. Our findings uncover a novel role for MAX in mitotic book-marking, highlighting its pivotal role in post-mitotic MYC recruitment and the re-establishment of high global transcription levels. These findings hold significant implications for medically relevant contexts, particularly when cell proliferation is of paramount importance 9 . We anticipate that the study of mitotic bookmarking by MYC and MAX and of the effects of anticancer drugs targeting MYC/MAX interactions in such process 10-12 will be relevant for our understanding of cancer and its potential treatments.

MYC and MAX drive the reactivation of the genome after mitosis