Multimerization of MYC shields stalled replication forks from RNA polymerase

Oncoproteins of the MYC family drive the development of numerous human tumors. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII). MYC proteins can also coordinate transcription with DNA replication and promote the repair of transcription-associated DNA damage, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from many of its binding sites in active promoters and forms multimeric, often sphere-like structures in response to perturbation of transcription elongation, mRNA splicing or inhibition of the proteasome. Multimerization is accompanied by a global change in the MYC interactome towards proteins involved in transcription termination and RNA processing. MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround FANCD2, ATR and BRCA1 proteins, which are located at stalled forks. MYC multimerization is triggered in a HUWE1 and ubiquitylation-dependent manner. At active promoters, MYC multimers block antisense transcription and stabilize FANCD2 association with chromatin. This limits DNA double-strand break formation during S-phase and allows rapid recovery from replication stress, suggesting that multimerization of MYC enables tumor cells to proliferate under stressful conditions Overall design: Sequencing of double-strand breaks in cells exposed to HU, BI8626 in presence or absence of MYC induction