Unknown,Transcriptomics,Genomics,Proteomics

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HDACs act on ribosomal DNA to control the yeast replication program and the competition between origins for limiting initiation factors [Mnase-seq]

ABSTRACT: In S. cerevisiae, replication timing is controlled by epigenetic mechanisms restricting the accessibility of origins to limiting initiation factors. About 30% of these origins are located within repetitive DNA sequences such as the ribosomal DNA (rDNA) array, but their regulation is poorly understood. Here, we have investigated how histone deacetylases (HDACs) control the replication program in budding yeast. This analysis revealed that two HDACs, Rpd3 and Sir2, control replication timing in an opposite manner. Whereas Rpd3 delays initiation at late origins, Sir2 is required for the timely activation of early origins. Moreover, Sir2 represses initiation at rDNA origins whereas Rpd3 counteracts this effect. Remarkably, deletion of SIR2 restored normal replication in rpd3 cells by reactivating rDNA origins. Together, these data indicate that HDACs control the replication timing program in budding yeast by modulating the ability of repeated origins to compete with single-copy origins for limiting initiation factors. MNase-seq analysis of nucleosome position in wt, sir2 and rpd3 cells, aligned against genomic DNA (sacCer3; *sorted_s3.bed) and rDNA sequences (*rdna_nucleosomes.bed)

ORGANISM(S): Saccharomyces cerevisiae

SUBMITTER: Philippe Pasero

PROVIDER: E-GEOD-57618 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Eukaryotic cells must inhibit re-initiation of DNA replication at each of the thousands of origins in their genome because re-initiation events can generate genomic alterations with extraordinary frequency. To minimize the probability of re-initiation from so many origins, cells use a battery of regulatory mechanisms that reduce the activity of replication initiation proteins. Given the global nature of these mechanisms, it has been presumed that all origins are inhibited identically. However, transiently disabling these mechanisms causes replication origins to re-initiate with diverse efficiencies, which do not correlate with known differences in the efficiency or timing of origin initiation during normal DNA replication. These observations suggest an additional local layer of replication control that can differentially influence how re-initiation is regulated at distinct origins. Principal Findings: We have identified novel genetic elements that are necessary for preferential re-initiation of two origins and sufficient to confer preferential re-initiation on heterologous origins when the control of re-initiation is partially deregulated. The elements do not enhance the S phase timing or efficiency of adjacent origins and thus are specifically acting as re-initiation promoters (RIPs). We have mapped the two RIPs to ~60bp AT rich sequences that act in a distance- and sequence-dependent manner. During the induction of re-replication, Mcm2-7 re-associates both with origins that preferentially re-initiate and origins that do not, suggesting that the RIP elements can overcome a block to re-initiation imposed after Mcm2-7 associates with origins. Conclusions/Significance: We have uncovered a local level of control in the block to re-initiation. This local control creates a complex genomic landscape of re-replication potential that is revealed when global mechanisms preventing re-replication are peeled away. Hence, if re-replication does contribute to genomic alterations, as has been speculated for cancer cells, some regions of the genome may be more susceptible to these alterations than others. 142 array CGH experiments are presented. Each experiment is done in experimental replicate. Cells grown as described in Richardson CD and Li JJ PLoS Genetics 2014. Ch1 samples taken from replicating (S phase) or re-replicating (M phase + 3/6 hour induced). Ch2 samples taken from M phase arrested DNA.

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HDACs act on ribosomal DNA to control the yeast replication program and the competition between origins for limiting initiation factors [Mnase-seq]

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