Title: A cytoskeletal function for PBRM1 reading methylated microtubules.

Authors: Karki, Menuka; Jangid, Rahul K; Anish, Ramakrishnan; Seervai, Riyad N H; Bertocchio, Jean-Philippe; Hotta, Takashi; Msaouel, Pavlos; Jung, Sung Yun; Grimm, Sandra L; Coarfa, Cristian; Weissman, Bernard E; Ohi, Ryoma; Verhey, Kristen J; Hodges, H Courtney; Burggren, Warren; Dere, Ruhee; Park, In Young; Prasad, B V Venkataram; Rathmell, W Kimryn; Walker, Cheryl L; Tripathi, Durga N

Published In Sci Adv, (2021 04)

Abstract: Epigenetic effectors "read" marks "written" on chromatin to regulate function and fidelity of the genome. Here, we show that this coordinated read-write activity of the epigenetic machinery extends to the cytoskeleton, with PBRM1 in the PBAF chromatin remodeling complex reading microtubule methyl marks written by the SETD2 histone methyltransferase. PBRM1 binds SETD2 methyl marks via BAH domains, recruiting PBAF components to the mitotic spindle. This read-write activity was required for normal mitosis: Loss of SETD2 methylation or pathogenic BAH domain mutations disrupt PBRM1 microtubule binding and PBAF recruitment and cause genomic instability. These data reveal PBRM1 functions beyond chromatin remodeling with domains that allow it to integrate chromatin and cytoskeletal activity via its acetyl-binding BD and methyl-binding BAH domains, respectively. Conserved coordinated activity of the epigenetic machinery on the cytoskeleton opens a previously unknown window into how chromatin remodeler defects can drive disease via both epigenetic and cytoskeletal dysfunction.

PubMed ID: 33811077

MeSH Terms: Chromatin Assembly and Disassembly; Chromatin/metabolism; Cytoskeleton/metabolism; Microtubules*/metabolism; Reading*