title: The U4/U6 recycling factor SART3 has histone chaperone activity and associates with USP15 to regulate H2B deubiquitination.
abstract: Post-translational modifications of histone proteins produce dynamic signals that regulate the structure and function of chromatin. Mono-ubiquitination of H2B in the histone tail (at Lys-123 in yeast or Lys-120 in humans) is a conserved modification that has been implicated in the regulation of transcription, replication, and DNA repair processes. In a search for direct effectors of ubH2B, we identified a deubiquitinating enzyme, Usp15, through affinity purification with a nonhydrolyzable ubH2B mimic. In the nucleus, Usp15 indirectly associates with the ubH2B E3 ligase, RNF20/RNF40, and directly associates with a component of the splicing machinery, SART3 (also known as TIP110 or p110). These physical interactions place Usp15 in the vicinity of actively transcribed DNA. Importantly we found that SART3 has previously unrecognized histone chaperone activities. SART3, but not the well-characterized histone chaperone Nap1, enhances Usp15 binding to ubH2B and facilitates deubiquitination of ubH2B in free histones but not in nucleosomes. These results suggest that SART3 recruits ubH2B, which may be evicted from DNA during transcription, for deubiquitination by Usp15. In light of the function played by SART3 in U4/U6 di-snRNP formation, our discovery points to a direct link between eviction-coupled erasure of the ubiquitin mark from ubH2B and co-transcriptional pre-mRNA splicing.
authors: From the Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado 80523.
authors: Lindsey
authors: L
authors: Long
authors: Joseph P
authors: JP
authors: Thelen
authors: Melonnie
authors: M
authors: Furgason
authors: Mahmood
authors: M
authors: Haj-Yahya
authors: Ashraf
authors: A
authors: Brik
authors: Dongmei
authors: D
authors: Cheng
authors: Junmin
authors: J
authors: Peng
authors: Tingting
authors: T
authors: Yao
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D002460:Cell Line; D006657:Histones / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D009707:Nucleosomes / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017414:Ribonucleoprotein, U4-U6 Small Nuclear / Q000378:metabolism*; D013379:Substrate Specificity; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D000951:Antigens, Neoplasm; D006657:Histones; D009707:Nucleosomes; D016601:RNA-Binding Proteins; D017414:Ribonucleoprotein, U4-U6 Small Nuclear; C416530:SART3 protein, human; C506646:RNF20 protein, human; C413363:RNF40 protein, human; D044767:Ubiquitin-Protein Ligases; C579226:USP15 protein, human; D064570:Ubiquitin-Specific Proteases
keywords: Deubiquitination; Histone Chaperone; Histone Modification; RNA Splicing; SART3; USP15; Ubiquitin; ubH2B