Abstract
This chapter focuses on the enzymes and mechanisms involved in lagging-strand DNA replication in eukaryotic cells. Recent structural and biochemical progress with DNA polymerase α-primase (Pol α) provides insights how each of the millions of Okazaki fragments in a mammalian cell is primed by the primase subunit and further extended by its polymerase subunit. Rapid kinetic studies of Okazaki fragment elongation by Pol δ illuminate events when the polymerase encounters the double-stranded RNA-DNA block of the preceding Okazaki fragment. This block acts as a progressive molecular break that provides both time and opportunity for the flap endonuclease 1 (FEN1) to access the nascent flap and cut it. The iterative action of Pol δ and FEN1 is coordinated by the replication clamp PCNA and produces a regulated degradation of the RNA primer, thereby preventing the formation of long-strand displacement flaps. Occasional long flaps are further processed by backup nucleases including Dna2.
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Acknowledgments
The research in the authors’ laboratory is supported by grants from the US National Institutes of Health (GM032431, GM083970, and GM118129 to P.B). J.S. was supported in part by a grant from the USA-Israel Binational Science Foundation (2013358).
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Stodola, J.L., Burgers, P.M. (2017). Mechanism of Lagging-Strand DNA Replication in Eukaryotes. In: Masai, H., Foiani, M. (eds) DNA Replication. Advances in Experimental Medicine and Biology, vol 1042. Springer, Singapore. https://doi.org/10.1007/978-981-10-6955-0_6
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