Graduation Year
2010
Document Type
Dissertation
Degree
Ph.D.
Degree Granting Department
Cancer Biology
Major Professor
Mark G. Alexandrow, Ph.D.
Committee Member
Lori A. Hazlehurst, Ph.D.
Committee Member
Gary W. Reuther, Ph.D.
Committee Member
Edward Seto, Ph.D.
Keywords
Cdt1, HDAC11, HBO1, chromatin, DNA replication
Abstract
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.
Scholar Commons Citation
Wong, Philip G., "Chromatin Unfolding by Cdt1 Regulates MCM Loading via Opposing Functions of HBO1 and HDAC11-Geminin" (2010). USF Tampa Graduate Theses and Dissertations.
https://digitalcommons.usf.edu/etd/3696
