title: QKI-mediated alternative splicing of the histone variant MacroH2A1 regulates cancer cell proliferation.
abstract: The histone variant macroH2A1 contains a carboxyl-terminal ∼30-kDa domain called a macro domain. MacroH2A1 is produced as one of two alternatively spliced forms, macroH2A1.1 and macroH2A1.2. While the macro domain of macroH2A1.1 can interact with NAD(+)-derived small molecules, such as poly(ADP-ribose), macroH2A1.2's macro domain cannot. Here, we show that changes in the alternative splicing of macroH2A1 pre-mRNA, which lead to a decrease in macroH2A1.1 expression, occur in a variety of cancers, including testicular, lung, bladder, cervical, breast, colon, ovarian, and endometrial. Furthermore, reintroduction of macroH2A1.1 suppresses the proliferation of lung and cervical cancer cells in a manner that requires the ability of macroH2A1.1 to bind NAD(+)-derived metabolites. MacroH2A1.1-mediated suppression of proliferation occurs, at least in part, through the reduction of poly(ADP-ribose) polymerase 1 (PARP-1) protein levels. By analyzing publically available expression and splicing microarray data, we identified splicing factors that correlate with alterations in macroH2A1 splicing. Using RNA interference, we demonstrate that one of these factors, QKI, regulates the alternative splicing of macroH2A1 pre-mRNA, resulting in increased levels of macroH2A1.1. Finally, we demonstrate that QKI expression is significantly reduced in many of the same cancer types that demonstrate a reduction in macroH2A1.1 splicing.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Golding 203, Bronx, NY 10461, USA.
authors.forename: Leonid
authors.initials: L
authors.lastname: Novikov
authors.forename: Jong Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Hongshan
authors.initials: H
authors.lastname: Chen
authors.forename: Hadassa
authors.initials: H
authors.lastname: Klerman
authors.forename: Abubakar S
authors.initials: AS
authors.lastname: Jalloh
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gamble
mesh_terms: D017398:Alternative Splicing; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009243:NAD / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D034622:RNA Interference; D012322:RNA Precursors / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D006657:Histones; C490832:QKI protein, human; D012322:RNA Precursors; D016601:RNA-Binding Proteins; C120756:macroH2A histone; D009243:NAD; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases