The retinoblastoma protein regulates pericentric heterochromatin.
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.
Isaac
Christian E
CE
Cancer Research Labs, 790 Commissioners Road East, London, Ontario, Canada, N6A 4L6.
Francis
Sarah M
SM
Martens
Alison L
AL
Julian
Lisa M
LM
Seifried
Laurie A
LA
Erdmann
Natalie
N
Binné
Ulrich K
UK
Harrington
Lea
L
Sicinski
Piotr
P
Bérubé
Nathalie G
NG
Dyson
Nicholas J
NJ
Dick
Frederick A
FA
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*
D006570:Heterochromatin; D006657:Histones; D016160:Retinoblastoma Protein; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine