Role for Merlin/NF2 in transcription elongation through interaction with the PAF complex

Roehrigh, A. E.; Klupsch, K.; Oses-Prieto, J. A.; Chaib, S.; Henderson, S.; Emmett, W.; Young, L. C.; Surinova, S.; Blees, A.; Pfeiffer, A.; Tijani, M.; Brunk, F.; Hartig, N.; Munoz-Alegre, M.; Hergovich, A.; Jennings, B.; Burlingame, A. L.; Rodriguez-Viciana, P.

doi:10.1101/717769

bioRxiv · 10.1101/717769

Role for Merlin/NF2 in transcription elongation through interaction with the PAF complex

Roehrigh, A. E.·Klupsch, K.·Oses-Prieto, J. A.·Chaib, S.·Henderson, S.·Emmett, W.·Young, L. C.·Surinova, S.·Blees, A.·Pfeiffer, A.·Tijani, M.·Brunk, F.·Hartig, N.·Munoz-Alegre, M.·Hergovich, A.·Jennings, B.·Burlingame, A. L.·Rodriguez-Viciana, P.

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Abstract

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing events and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions at the cell cortex and nucleus and is a key mediator of contact inhibition. Here we provide a direct link between nuclear Merlin and transcription elongation controlled by cell-cell adhesion. Merlin interacts with the PAFC in a cell density-dependent manner and tumour-derived inactivating mutations in both Merlin and CDC73 mutually disrupt their interaction. Growth suppression by Merlin requires CDC73 and Merlin regulates PAFC association with chromatin in a subset of genes. We also identify by CDC73 affinity-proteomics a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, nuclear Merlin is part of a tumour suppressor network which coordinates postinitiation steps of the transcription cycle of genes mediating in contact inhibition.

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Roehrigh, A. E., Klupsch, K., Oses-Prieto, J. A., Chaib, S., Henderson, S., Emmett, W., Young, L. C., Surinova, S., Blees, A., Pfeiffer, A., Tijani, M., Brunk, F., Hartig, N., Munoz-Alegre, M., Hergovich, A., Jennings, B., Burlingame, A. L., Rodriguez-Viciana, P.. 2019-07-28. Role for Merlin/NF2 in transcription elongation through interaction with the PAF complex. https://doi.org/10.1101/717769

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