title: The retinoblastoma protein regulates pericentric heterochromatin.
abstract: The retinoblastoma protein (pRb) has been proposed to regulate cell cycle progression in part through its ability to interact with enzymes that modify histone tails and create a repressed chromatin structure. We created a mutation in the murine Rb1 gene that disrupted pRb's ability to interact with these enzymes to determine if it affected cell cycle control. Here, we show that loss of this interaction slows progression through mitosis and causes aneuploidy. Our experiments reveal that while the LXCXE binding site mutation does not disrupt pRb's interaction with the Suv4-20h histone methyltransferases, it dramatically reduces H4-K20 trimethylation in pericentric heterochromatin. Disruption of heterochromatin structure in this chromosomal region leads to centromere fusions, chromosome missegregation, and genomic instability. These results demonstrate the surprising finding that pRb uses the LXCXE binding cleft to control chromatin structure for the regulation of events beyond the G(1)-to-S-phase transition.
authors.affiliation: Cancer Research Labs, 790 Commissioners Road East, London, Ontario, Canada, N6A 4L6.
authors.forename: Christian E
authors.initials: CE
authors.lastname: Isaac
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Francis
authors.forename: Alison L
authors.initials: AL
authors.lastname: Martens
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Julian
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Seifried
authors.forename: Natalie
authors.initials: N
authors.lastname: Erdmann
authors.forename: Ulrich K
authors.initials: UK
authors.lastname: Binné
authors.forename: Lea
authors.initials: L
authors.lastname: Harrington
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.forename: Nathalie G
authors.initials: NG
authors.lastname: Bérubé
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dyson
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D002503:Centromere / Q000378:metabolism*; D006570:Heterochromatin / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation; D051379:Mice; D008817:Mice, Mutant Strains; D008938:Mitosis / Q000235:genetics*; D009154:Mutation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D006570:Heterochromatin; D006657:Histones; D016160:Retinoblastoma Protein; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine