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G-quadruplexes (G4s) appear in both DNA and RNA, and recent studies implicate these structures in various biological reactions including telomere regulation, epigenome regulation, transcription, translation, splicing, viral maintenance and functions, transpositions, repair and recombination. In this seminar I would like to introduce our recent studies on its roles in regulation of DNA replication.
Genome needs to replicate itself once and only once with minimum error in a given cell cycle. This task is hard to achieve, given the size of the genome, the time allotted, and various threats that could interfere with the process. Therefore, the rules of DNA replication may be fairly relaxed once cells make commitment to S phase. Indeed, origin choice appears to be stochastic even in yeasts with smaller genomes. Bacteria, in contrast, utilize a single, highly efficient origin for initiation. This is a very efficient mode of replication, but is more vulnerable to environmental changes. An alternative mode of replication of E. coli occurs on R-loops. R-loop formation is facilitated by the presence of multiple G-tracts, that can form G4 structure. The presence of G4-forming sequences near significant proportions of replication origins, identified through genome-wide analyses in higher eukaryotes including human, was reported. We are exploring now how these non-B DNA structures could be involved in potential mechanisms for relaxed modes of initiation of DNA replication.
The replication timing regulation involves suppression of origin firing by Rif1 which recognizes and binds to G4 on the chromosome. Timing regulation is not essential for completion of S phase, but may coordinate the replication process with other chromosome events including replication, epigenome regulation and DNA repair/ mutagenesis. I will discuss the roles of G4 binding, oligomerization and nuclear membrane localization of Rif1 in its ability to regulate replication timing.
Our results indicate that non-B DNA structures, such as G4 and RNA-DNA hybrid, now emerge as important genome signature that may contribute to robust and plastic nature of genome functions.
Hisao Masai, Ph.D.
Director, Genome Dynamics Project, Department of Genome Medicine,
Tokyo Metropolitan Institute of Medical Science (TMiMS)
12:00 pm on Zoom
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