MYC multimers shield stalled replication forks from RNA polymerase

Daniel Solvie, Apoorva Baluapuri, Leonie Uhl, Daniel Fleischhauer, Theresa Endres, Dimitrios Papadopoulos, Amel Aziba, Abdallah Gaballa, Ivan Mikicic, Ekaterina Isaakova, Celeste Giansanti, Jennifer Jansen, Marvin Jungblut, Teresa Klein, Christina Schülein-Völk, Hans Maric, Sören Doose, Markus Sauer, Petra Beli, Andreas Rosenwald, Matthias Dobbelstein, Elmar Wolf () and Martin Eilers ()
Additional contact information
Daniel Solvie: University of Würzburg
Apoorva Baluapuri: University of Würzburg
Leonie Uhl: University of Würzburg
Daniel Fleischhauer: University of Würzburg
Theresa Endres: University of Würzburg
Dimitrios Papadopoulos: University of Würzburg
Amel Aziba: University of Würzburg
Abdallah Gaballa: University of Würzburg
Ivan Mikicic: Institute of Molecular Biology (IMB)
Ekaterina Isaakova: Institute of Molecular Biology (IMB)
Celeste Giansanti: University of Göttingen
Jennifer Jansen: University of Göttingen
Marvin Jungblut: University of Würzburg
Teresa Klein: University of Würzburg
Christina Schülein-Völk: University of Würzburg
Hans Maric: University of Würzburg
Sören Doose: University of Würzburg
Markus Sauer: University of Würzburg
Petra Beli: Institute of Molecular Biology (IMB)
Andreas Rosenwald: Institute of Pathology, University of Würzburg
Matthias Dobbelstein: University of Göttingen
Elmar Wolf: University of Würzburg
Martin Eilers: University of Würzburg

Nature, 2022, vol. 612, issue 7938, 148-155

Abstract: Abstract Oncoproteins of the MYC family drive the development of numerous human tumours1. In unperturbed cells, MYC proteins bind to nearly all active promoters and control transcription by RNA polymerase II2,3. MYC proteins can also coordinate transcription with DNA replication4,5 and promote the repair of transcription-associated DNA damage6, 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 forks7,8. MYC multimerization is triggered in a HUWE16 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, suggesting that the multimerization of MYC enables tumour cells to proliferate under stressful conditions.

Date: 2022
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DOI: 10.1038/s41586-022-05469-4

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