mSin3-associated protein, mSds3, is essential for pericentric heterochromatin formation and chromosome segregation in mammalian cells.
The histone code guides many aspects of chromosome biology including the equal distribution of chromosomes during cell division. In the chromatin domains surrounding the centromere, known as pericentric heterochromatin, histone modifications, particularly deacetylation and methylation, appear to be essential for proper chromosome segregation. However, the specific factors and their precise roles in this highly orchestrated process remain under active investigation. Here, we report that germ-line or somatic deletion of mSds3, an essential component of the functional mSin3/HDAC corepressor complex, generates a cell-lethal condition associated with rampant aneuploidy, defective karyokinesis, and consequently, a failure of cytokinesis. mSds3-deficient cells fail to deacetylate and methylate pericentric heterochromatin histones and to recruit essential heterochromatin-associated proteins, resulting in aberrant associations among heterologous chromosomes via centromeric regions and consequent failure to properly segregate chromosomes. Mutant mSds3 molecules that are defective in mSin3 binding fail to rescue the mSds3 null phenotypes. On the basis of these findings, we propose that mSds3 and its associated mSin3/HDAC components play a central role in initiating the cascade of pericentric heterochromatin-specific modifications necessary for the proper distribution of chromosomes during cell division in mammalian cells.
David
Gregory
G
Departments of Medical Oncology, Medicine, and Genetics, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Turner
Garth M
GM
Yao
Yao
Y
Protopopov
Alexei
A
DePinho
Ronald A
RA
D000107:Acetylation; D000782:Aneuploidy; D000818:Animals; D001755:Blastocyst / Q000502:physiology; D002265:Carboxylic Ester Hydrolases / Q000235:genetics* / Q000378:metabolism*; D002478:Cells, Cultured; D020090:Chromosome Segregation; D005347:Fibroblasts / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006570:Heterochromatin / Q000502:physiology*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D019426:Integrases / Q000235:genetics; D008322:Mammals / Q000235:genetics; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D016615:Telomere / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics
D006570:Heterochromatin; D006657:Histones; D012097:Repressor Proteins; C071731:SIN3 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D002265:Carboxylic Ester Hydrolases; C430718:SDS3 protein, S cerevisiae; D006655:Histone Deacetylases