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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

Moderate over-expression of ABF2 does not trigger the RTG response.RNA blots of CIT2 steady-state levels, from cells grown under glucose limitation in chemostats. The relevant genotype and strain background are shown above each lane. RPS16A levels indicate loading.
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pgen-1000047-g003: Moderate over-expression of ABF2 does not trigger the RTG response.RNA blots of CIT2 steady-state levels, from cells grown under glucose limitation in chemostats. The relevant genotype and strain background are shown above each lane. RPS16A levels indicate loading.

Mentions: If mitochondria do not function properly a retrograde (RTG) response leads to elevated (∼10-fold) CIT2 levels [21],[22]. As expected, in ρ° cells, which lack mtDNA, the CIT2 RNA level was increased ∼5-fold over the level in ρ+ cells (Figure 3). In contrast, we found that CIT2 mRNA levels are not elevated in cells over-expressing ABF2. Instead, CIT2 levels are reduced by ∼2-fold (Figure 3). Thus, the mitochondria of cells over-expressing ABF2 are not dysfunctional. Using a colony sectoring assay [23], we also found that the frequency of chromosome loss was 1.66% (n = 3,004) for CEN-ABF2+ transformants, compared to 1.73% (n = 2,657) for the empty vector transformants. Therefore, over-expression of ABF2 does not cause gross genome instability.


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)

Moderate over-expression of ABF2 does not trigger the RTG response.RNA blots of CIT2 steady-state levels, from cells grown under glucose limitation in chemostats. The relevant genotype and strain background are shown above each lane. RPS16A levels indicate loading.
© Copyright Policy
Related In: Results  -  Collection

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

pgen-1000047-g003: Moderate over-expression of ABF2 does not trigger the RTG response.RNA blots of CIT2 steady-state levels, from cells grown under glucose limitation in chemostats. The relevant genotype and strain background are shown above each lane. RPS16A levels indicate loading.
Mentions: If mitochondria do not function properly a retrograde (RTG) response leads to elevated (∼10-fold) CIT2 levels [21],[22]. As expected, in ρ° cells, which lack mtDNA, the CIT2 RNA level was increased ∼5-fold over the level in ρ+ cells (Figure 3). In contrast, we found that CIT2 mRNA levels are not elevated in cells over-expressing ABF2. Instead, CIT2 levels are reduced by ∼2-fold (Figure 3). Thus, the mitochondria of cells over-expressing ABF2 are not dysfunctional. Using a colony sectoring assay [23], we also found that the frequency of chromosome loss was 1.66% (n = 3,004) for CEN-ABF2+ transformants, compared to 1.73% (n = 2,657) for the empty vector transformants. Therefore, over-expression of ABF2 does not cause gross genome instability.

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