Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system , two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication profiles of these cells. Both mechanisms are thought to act through specific recruitment of a rate-limiting initiation factor, Dbf4-dependent kinase (DDK), to a subset of licensed replication origins. Fkh1/2 is responsible for stimulation of most early-firing origins, except for centromere (CEN)-proximal origins that recruit DDK via the kinetochore protein Ctf19, which is required for their early firing. The C-terminus of Dbf4 has been implicated in its recruitment to origins via both the Fkh1/2 and Ctf19 mechanisms. Here, we show that the Zn-finger motif within the C-terminus is specifically required for Dbf4 recruitment to CENs to stimulate CEN-proximal/Ctf19-dependent origins, whereas stimulation of origins via the Fkh1/2 pathway remains largely intact. These findings re-open the question of exactly how Fkh1/2 and DDK act together to stimulate replication origin initiation.
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| http://dx.doi.org/10.3390/genes13122202 | DOI Listing |
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Interactions between Fkh1 monomers stabilize its binding to DNA replication origins.
J Biol Chem
August 2023
Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia. Electronic address:
Eukaryotic DNA replication is initiated from multiple genomic origins, which can be broadly categorized as firing early or late in the S phase. Several factors can influence the temporal usage of origins to determine the timing of their firing. In budding yeast, the Forkhead family proteins Fkh1 and Fkh2 bind to a subset of replication origins and activate them at the beginning of the S phase.
View Article and Find Full Text PDFDbf4 Zn-Finger Motif Is Specifically Required for Stimulation of Ctf19-Activated Origins in .
Genes (Basel)
November 2022
Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, 1050 Childs Way, Los Angeles, CA 90089-2910, USA.
Eukaryotic genomes are replicated in spatiotemporal patterns that are stereotypical for individual genomes and developmental profiles. In the model system , two primary mechanisms determine the preferential activation of replication origins during early S phase, thereby largely defining the consequent replication profiles of these cells. Both mechanisms are thought to act through specific recruitment of a rate-limiting initiation factor, Dbf4-dependent kinase (DDK), to a subset of licensed replication origins.
View Article and Find Full Text PDFRpd3 regulates single-copy origins independently of the rDNA array by opposing Fkh1-mediated origin stimulation.
Proc Natl Acad Sci U S A
October 2022
Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089-2910.
Eukaryotic chromosomes are organized into structural and functional domains with characteristic replication timings, which are thought to contribute to epigenetic programming and genome stability. Differential replication timing results from epigenetic mechanisms that positively and negatively regulate the competition for limiting replication initiation factors. Histone deacetylase Sir2 negatively regulates initiation of the multicopy (∼150) rDNA origins, while Rpd3 histone deacetylase negatively regulates firing of single-copy origins.
View Article and Find Full Text PDFIdentification of Fkh1 and Fkh2 binding site variants associated with dynamically bound DNA elements including replication origins.
Nucleus
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a Molecular and Computational Biology Program , University of Southern California, Los Angeles , CA , USA.
Forkhead Box (Fox) DNA binding proteins control multiple genome activities, including transcription, replication, and repair. These activities are organized spatially and temporally in the nucleus, and Fox proteins Fkh1 and Fkh2 have emerged as regulators of long-range chromosomal interactions involved with these activities, such as the clustering of replication origins programmed for early initiation. Fkh1 and Fkh2 bind a subset of replication origins and are thought to dimerize to mediate long-range chromosomal contacts between these origins.
View Article and Find Full Text PDFRecruitment of Fkh1 to replication origins requires precisely positioned Fkh1/2 binding sites and concurrent assembly of the pre-replicative complex.
PLoS Genet
January 2017
Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
In budding yeast, activation of many DNA replication origins is regulated by their chromatin environment, whereas others fire in early S phase regardless of their chromosomal location. Several location-independent origins contain at least two divergently oriented binding sites for Forkhead (Fkh) transcription factors in close proximity to their ARS consensus sequence. To explore whether recruitment of Forkhead proteins to replication origins is dependent on the spatial arrangement of Fkh1/2 binding sites, we changed the spacing and orientation of the sites in early replication origins ARS305 and ARS607.
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