Chromatin unfolding by Cdt1 regulates MCM loading via opposing functions of HBO1 and HDAC11-geminin.
The efficiency of metazoan origins of DNA replication is known to be enhanced by histone acetylation near origins. Although this correlates with increased MCM recruitment, the mechanism by which such acetylation regulates MCM loading is unknown. We show here that Cdt1 induces large-scale chromatin decondensation that is required for MCM recruitment. This process occurs in G₁, is suppressed by Geminin, and requires HBO1 HAT activity and histone H4 modifications. HDAC11, which binds Cdt1 and replication origins during S-phase, potently inhibits Cdt1-induced chromatin unfolding and re-replication, suppresses MCM loading and binds Cdt1 more efficiently in the presence of Geminin. We also demonstrate that chromatin at endogenous origins is more accessible in G₁ relative to S-phase. These results provide evidence that histone acetylation promotes MCM loading via enhanced chromatin accessibility. This process is regulated positively by Cdt1 and HBO1 in G₁ and repressed by Geminin-HDAC11 association with Cdt1 in S-phase, and represents a novel form of replication licensing control.
Wong
Philip G
PG
Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Glozak
Michele A
MA
Cao
Thinh V
TV
Vaziri
Cyrus
C
Seto
Edward
E
Alexandrow
Mark
M
D000107:Acetylation; D018797:Cell Cycle Proteins / Q000378:metabolism* / Q000502:physiology; D002843:Chromatin / Q000737:chemistry / Q000502:physiology*; D016193:G1 Phase; D064248:Geminin; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000378:metabolism* / Q000502:physiology; D006655:Histone Deacetylases / Q000378:metabolism* / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D026341:Minichromosome Maintenance 1 Protein / Q000378:metabolism*; D016196:S Phase
C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D002843:Chromatin; C577995:GMNN protein, human; D064248:Geminin; D006657:Histones; D026341:Minichromosome Maintenance 1 Protein; D051548:Histone Acetyltransferases; C496553:KAT7 protein, human; C462506:HDAC11 protein, human; D006655:Histone Deacetylases