The tudor protein survival motor neuron (SMN) is a chromatin-binding protein that interacts with methylated histone H3 lysine 79

Abstract

SummarySpinal muscular atrophy (SMA) is a muscular disease characterized by the death of motoneurons, and is a major genetic cause of infant mortality. Mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), are responsible for the disease. SMN belongs to the Tudor domain protein family, whose members are known to interact with methylated arginine (R) or lysine (K) residues. SMN has well-defined roles in the metabolism of small non-coding ribonucleoproteins (snRNPs) and spliceosome activity. We previously showed that SMN relocated to damaged interphase centromeres, together with the Cajal-body-associated proteins coilin and fibrillarin, during the so-called interphase centromere damage response (iCDR). Here we reveal that SMN is a chromatin-binding protein that specifically interacts with methylated histone H3K79, a gene expression-and splicing-associated histone modification. SMN relocation to damaged centromeres requires its functional Tudor domain and activity of the H3K79 methyltransferase DOT1L. In vitro pulldown assays showed that SMN interacts with H3K79me1,2 at its functional Tudor domain. Chromatin immunoprecipitation confirmed that SMN binds to H3K79me1,2-containing chromatin in iCDR-induced cells. These data reveal a novel SMN property in the detection of specific chromatin modifications, and shed new light on the involvement of a putative epigenetic dimension to the occurrence of SMA.

Rescue of gene-expression changes in an induced mouse model of spinal muscular atrophy by an antisense oligonucleotide that promotes inclusion of SMN2 exon 7

“…SMN itself is recruited, through its N-terminal Tudor domain, to dimethylated histone H3K79 in the setting of the interphase centromere damage response [28]. Whether SMN is involved in executing this response or other forms of DNA repair, such as double-strand break repair, known to be mediated by another Tudor-domain protein, 53BP1, in an H3K79me-dependent manner [29], is a question that warrants further investigation.…”

The emerging roles of DOT1L in leukemia and normal development

“…58 The finding that the SMN protein recognizes methylated H3K79 indicates that there may be an epigenetic dimension to spinal muscular atrophy and that DOT1L may be important for motor neuron function. 57 Future research should determine the specific interplay and whether this function of DOT1L is confirmed in vivo. Several other key questions need further attention.…”

“…SMN recognizes and interacts with methylated H3K79 in HeLa cells. 57 SMN is needed for the health and survival of motor neurons, and deficient SMN protein levels leads to spinal muscular atrophy. 58 The finding that the SMN protein recognizes methylated H3K79 indicates that there may be an epigenetic dimension to spinal muscular atrophy and that DOT1L may be important for motor neuron function.…”

Advances in Therapeutic Development for Spinal Muscular Atrophy

“…The SMN protein contains several functional domains including Gemin2-binding, nucleic acid binding, Tudor, self-association and cal-pain cleavage (Figure 1A) [8,9]. The interaction of SMN with Gemin2 has been suggested to be important for several SMN functions including small nuclear ribonucleoprotein (snRNP) biogenesis [19], signal recognition particle biogenesis [20], DNA recombination [21], motor neuron trafficking of mRNAs [22] and translation regulation [23].…”

“…It remains to be seen if gems have specific functions or whether they are the signatures of an ordered nuclear organization forced by the spatial and temporal arrangement of other macromolecules. Other less studied SMN functions include detection of specific chromatin modifications [9], transcription [65,66], translation [23], signal transduction [67], stress granule formation [68] and macromolecular trafficking [69,70]. Motor neurons are particularly susceptible to the loss of SMN protein, although the reasons underlying this susceptibility are not well understood.…”