Graduation Year

2010

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Cancer Biology

Major Professor

Mark G. Alexandrow, Ph.D.

Co-Major Professor

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.

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