Stress-induced multimerization of MYC shields stalled replication forks from RNA Polymerase

Oncoproteins of the MYC family drive the development of numerous human tumors1-4. In unperturbed cells, MYC proteins bind to virtually all active promoters and control transcription by RNA Polymerase II (RNAPII)2,3,5,6. MYC proteins can also coordinate transcription with DNA replication7-9 and promote the repair of transcription-associated DNA damage10, but how they exert these mechanistically diverse functions is unknown. Here we show that MYC dissociates from most of its binding sites in promoters and forms stable multimeric shell-like structures in response to perturbation of transcription elongation, mRNA splicing, or DNA replication. MYC multimers recruit interacting proteins that can promote transcription termination into their shells. Intriguingly, MYC multimers accumulate on chromatin immediately adjacent to stalled replication forks and surround the FANCD2, ATR and BRCA1 proteins, which are located at stalled forks11,12. MYC multimers accumulate ubiquitylated proteins and their formation depends on the HUWE1 ubiquitin ligase10,13. In response to replication stress, HUWE1 and MYC limit phosphorylation of the single-strand binding protein, RPA. We propose that localised multimerisation of MYC creates a transcription termination zone around stalled replication forks that limits checkpoint signalling in response to transcriptional and replication stress, allowing tumor cells to actively proliferate under stressful conditions Overall design: Chromatin binding of MYC, FANCD2 and ATR alsong with gene expression data after variation chemical treatments