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An increase in mitochondrial DNA promotes nuclear DNA replication in yeast.

Blank HM, Li C, Mueller JE, Bogomolnaya LM, Bryk M, Polymenis M - PLoS Genet. (2008)

Bottom Line: The Sir2p NAD+-dependent de-acetylase antagonizes this mitochondrial role.We found that cells with increased mitochondrial DNA have reduced Sir2p levels bound at origins of DNA replication in the nucleus, accompanied with increased levels of K9, K14-acetylated histone H3 at those origins.They also suggest that cellular metabolism may impact on chromatin modifications to regulate the activity of origins of DNA replication.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.

ABSTRACT
Coordination between cellular metabolism and DNA replication determines when cells initiate division. It has been assumed that metabolism only plays a permissive role in cell division. While blocking metabolism arrests cell division, it is not known whether an up-regulation of metabolic reactions accelerates cell cycle transitions. Here, we show that increasing the amount of mitochondrial DNA accelerates overall cell proliferation and promotes nuclear DNA replication, in a nutrient-dependent manner. The Sir2p NAD+-dependent de-acetylase antagonizes this mitochondrial role. We found that cells with increased mitochondrial DNA have reduced Sir2p levels bound at origins of DNA replication in the nucleus, accompanied with increased levels of K9, K14-acetylated histone H3 at those origins. Our results demonstrate an active role of mitochondrial processes in the control of cell division. They also suggest that cellular metabolism may impact on chromatin modifications to regulate the activity of origins of DNA replication.

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Related in: MedlinePlus

A schematic of the model suggested by our data.An increase of mtDNA by moderate over-expression of Abf2p promotes mitochondrial functions, which in turn accelerate cell proliferation and DNA replication. The NAD+-dependent de-acetylase Sir2p antagonizes initiation of DNA replication. Cells over-expressing Abf2p have decreased levels of Sir2p at origins of DNA replication (ARS), and higher levels of acetylated K9, K14 histone H3 residues (Ac). Additional mechanisms likely contribute to the overall positive effects on cell proliferation and DNA replication in cells with higher mtDNA levels.
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pgen-1000047-g010: A schematic of the model suggested by our data.An increase of mtDNA by moderate over-expression of Abf2p promotes mitochondrial functions, which in turn accelerate cell proliferation and DNA replication. The NAD+-dependent de-acetylase Sir2p antagonizes initiation of DNA replication. Cells over-expressing Abf2p have decreased levels of Sir2p at origins of DNA replication (ARS), and higher levels of acetylated K9, K14 histone H3 residues (Ac). Additional mechanisms likely contribute to the overall positive effects on cell proliferation and DNA replication in cells with higher mtDNA levels.

Mentions: To answer if binding of Sir2p at the rDNA origins depends on the presence of mtDNA, we then examined the corresponding ρ− strains (Figure S6). Notably, in both ABF2+ or 3xABF2+ ρ− cells Sir2p levels are increased at the rDNA ARS by ∼2-fold (Figure S6). Thus, the level of Sir2p bound at the rDNA ARS elements is inversely related to the amount of mtDNA in the cell. It appears that some mitochondrial function that depends on mtDNA limits the association of Sir2p with origins of replication. Together, these results identify physical changes associated with active origins of DNA replication in the nucleus, resulting from an increase in the amount of the mitochondrial genome (Figure 10).


An increase in mitochondrial DNA promotes nuclear DNA replication in yeast.

Blank HM, Li C, Mueller JE, Bogomolnaya LM, Bryk M, Polymenis M - PLoS Genet. (2008)

A schematic of the model suggested by our data.An increase of mtDNA by moderate over-expression of Abf2p promotes mitochondrial functions, which in turn accelerate cell proliferation and DNA replication. The NAD+-dependent de-acetylase Sir2p antagonizes initiation of DNA replication. Cells over-expressing Abf2p have decreased levels of Sir2p at origins of DNA replication (ARS), and higher levels of acetylated K9, K14 histone H3 residues (Ac). Additional mechanisms likely contribute to the overall positive effects on cell proliferation and DNA replication in cells with higher mtDNA levels.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2289842&req=5

pgen-1000047-g010: A schematic of the model suggested by our data.An increase of mtDNA by moderate over-expression of Abf2p promotes mitochondrial functions, which in turn accelerate cell proliferation and DNA replication. The NAD+-dependent de-acetylase Sir2p antagonizes initiation of DNA replication. Cells over-expressing Abf2p have decreased levels of Sir2p at origins of DNA replication (ARS), and higher levels of acetylated K9, K14 histone H3 residues (Ac). Additional mechanisms likely contribute to the overall positive effects on cell proliferation and DNA replication in cells with higher mtDNA levels.
Mentions: To answer if binding of Sir2p at the rDNA origins depends on the presence of mtDNA, we then examined the corresponding ρ− strains (Figure S6). Notably, in both ABF2+ or 3xABF2+ ρ− cells Sir2p levels are increased at the rDNA ARS by ∼2-fold (Figure S6). Thus, the level of Sir2p bound at the rDNA ARS elements is inversely related to the amount of mtDNA in the cell. It appears that some mitochondrial function that depends on mtDNA limits the association of Sir2p with origins of replication. Together, these results identify physical changes associated with active origins of DNA replication in the nucleus, resulting from an increase in the amount of the mitochondrial genome (Figure 10).

Bottom Line: The Sir2p NAD+-dependent de-acetylase antagonizes this mitochondrial role.We found that cells with increased mitochondrial DNA have reduced Sir2p levels bound at origins of DNA replication in the nucleus, accompanied with increased levels of K9, K14-acetylated histone H3 at those origins.They also suggest that cellular metabolism may impact on chromatin modifications to regulate the activity of origins of DNA replication.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas, United States of America.

ABSTRACT
Coordination between cellular metabolism and DNA replication determines when cells initiate division. It has been assumed that metabolism only plays a permissive role in cell division. While blocking metabolism arrests cell division, it is not known whether an up-regulation of metabolic reactions accelerates cell cycle transitions. Here, we show that increasing the amount of mitochondrial DNA accelerates overall cell proliferation and promotes nuclear DNA replication, in a nutrient-dependent manner. The Sir2p NAD+-dependent de-acetylase antagonizes this mitochondrial role. We found that cells with increased mitochondrial DNA have reduced Sir2p levels bound at origins of DNA replication in the nucleus, accompanied with increased levels of K9, K14-acetylated histone H3 at those origins. Our results demonstrate an active role of mitochondrial processes in the control of cell division. They also suggest that cellular metabolism may impact on chromatin modifications to regulate the activity of origins of DNA replication.

Show MeSH
Related in: MedlinePlus