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.

No abstract

1 Centromeric protein B (CENP-B) is a major constituent of the centromere. It is a DNA binding 2 protein that recognizes a specific 17-nt sequence present in the centromeric alphoid satellite repeats. 3 CENP-B importance for centromere stability has only been revealed recently. In addition to its DNA 4 binding properties, CENP-B interacts with the histone H3 variant CENP-A and CENP-C. These 5interactions confer a mechanical strength to the kinetochore that enables accurate sister chromatids 6 segregation to avoid aneuploidy. Therefore, understanding the mechanisms that regulate CENP-B 7 stability at the centromere is a major unresolved issue for the comprehension of centromere function. 8In this study, we demonstrate that lysine K402 of CENP-B is a substrate for SUMO post-translational 9modifications. We show that K402 regulates CENP-B stability at centromeres through a 10SUMOylation/ubiquitination and proteasomal-dependent degradation mechanism involving the 11 SUMO-Targeted Ubiquitin E3 Ligase RNF4/SNURF. Our study describes SUMOylation of CENP-B as a 12 major post-translational modification involved in centromere dynamics. 13 14 degradation mechanism involving the SUMO-Targeted Ubiquitin Ligase (STUbL) RNF4/SNURF

No abstract

No abstract