title: Human UBN1 is an ortholog of yeast Hpc2p and has an essential role in the HIRA/ASF1a chromatin-remodeling pathway in senescent cells.
abstract: Cellular senescence is an irreversible proliferation arrest, tumor suppression process and likely contributor to tissue aging. Senescence is often characterized by domains of facultative heterochromatin, called senescence-associated heterochromatin foci (SAHF), which repress expression of proliferation-promoting genes. Given its likely contribution to tumor suppression and tissue aging, it is essential to identify all components of the SAHF assembly pathway. Formation of SAHF in human cells is driven by a complex of histone chaperones, namely, HIRA and ASF1a. In yeast, the complex orthologous to HIRA/ASF1a contains two additional proteins, Hpc2p and Hir3p. Using a sophisticated approach to search for remote orthologs conserved in multiple species through evolution, we identified the HIRA-associated proteins, UBN1 and UBN2, as candidate human orthologs of Hpc2p. We show that the Hpc2-related domain of UBN1, UBN2, and Hpc2p is an evolutionarily conserved HIRA/Hir-binding domain, which directly interacts with the N-terminal WD repeats of HIRA/Hir. UBN1 binds to proliferation-promoting genes that are repressed by SAHF and associates with histone methyltransferase activity that methylates lysine 9 of histone H3, a site that is methylated in SAHF. UBN1 is indispensable for formation of SAHF. We conclude that UBN1 is an ortholog of yeast Hpc2p and a novel regulator of senescence.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
authors.forename: Gowrishankar
authors.initials: G
authors.lastname: Banumathy
authors.forename: Neeta
authors.initials: N
authors.lastname: Somaiah
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
authors.forename: Yong
authors.initials: Y
authors.lastname: Tang
authors.forename: Jason
authors.initials: J
authors.lastname: Hoffmann
authors.forename: Mark
authors.initials: M
authors.lastname: Andrake
authors.forename: Hugo
authors.initials: H
authors.lastname: Ceulemans
authors.forename: David
authors.initials: D
authors.lastname: Schultz
authors.forename: Ronen
authors.initials: R
authors.lastname: Marmorstein
authors.forename: Peter D
authors.initials: PD
authors.lastname: Adams
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D016922:Cellular Senescence; D042002:Chromatin Assembly and Disassembly; D017124:Conserved Sequence; D019925:Cyclin A / Q000235:genetics; D056751:Cyclin A2; D019143:Evolution, Molecular; D006570:Heterochromatin / Q000378:metabolism; D056488:Histone Chaperones; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism; D008780:Methyltransferases / Q000378:metabolism; D018832:Molecular Chaperones; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D020449:Repetitive Sequences, Amino Acid; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D015534:Trans-Activators / Q000737:chemistry*; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*
chemical_list: C491641:ASF1A protein, human; C503721:CCNA2 protein, human; D018797:Cell Cycle Proteins; D019925:Cyclin A; D056751:Cyclin A2; C086057:HIRA protein, human; C077306:HPC2 protein, S cerevisiae; D006570:Heterochromatin; D056488:Histone Chaperones; D018832:Molecular Chaperones; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C406814:UBN1 protein, human; D008780:Methyltransferases