The TUDOR domain of SMN is an H3K79me1 histone mark reader

Abstract

Spinal Muscle Atrophy (SMA) is the leading genetic cause of infant mortality and results from the loss of functional Survival Motor Neuron (SMN) protein by either deletion or mutation of the SMN1 gene. SMN is characterized by a central TUDOR domain, which mediates the association of SMN with arginine methylated (Rme) partners, such as COILIN, FIBRILLARIN, and RNApolII. Herein, we biochemically demonstrate that SMN also associates with histone H3 monomethylated on lysine 79 (H3K79me1), defining SMN as the first known H3K79me1 histone mark reader, and thus the first histone mark reader to recognize both methylated arginine and lysine residues. Mutational analyzes provide evidence that SMNTUDOR associates with H3 via an aromatic cage. Importantly, most SMNTUDOR mutants found in SMA (SMNST) patients fail to associate with H3K79me1. Summary BlurbSpinal Muscle Atrophy (SMA) is caused by mutation or deletion of SMN1 gene. Survival Motor Neuron (SMN) protein associates with histone H3 mono-methylated on lysine 79 (H3K79me1) through its central TUDOR domain. SMA-linked mutations occur within the TUDOR domain and prevent association with histone H3.