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Fast and efficient DNA replication with purified human proteins

Nature (London), 2022-06, Vol.606 (7912), p.204-210 [Peer Reviewed Journal]

2022. The Author(s), under exclusive licence to Springer Nature Limited. ;Copyright Nature Publishing Group Jun 2, 2022 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-022-04759-1 ;PMID: 35585232

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Title:
Fast and efficient DNA replication with purified human proteins
Author: Baris, Yasemin ; Taylor, Martin R G ; Aria, Valentina ; Yeeles, Joseph T P
Subjects: Cdc45 protein ; Chromosomes ; Deoxyribonucleic acid ; DNA ; DNA - biosynthesis ; DNA Helicases - isolation & purification ; DNA Helicases - metabolism ; DNA polymerase ; DNA primase ; DNA Replication ; DNA-Binding Proteins - isolation & purification ; DNA-Binding Proteins - metabolism ; DNA-directed DNA polymerase ; DNA-Directed DNA Polymerase - chemistry ; DNA-Directed DNA Polymerase - isolation & purification ; Humans ; Multienzyme Complexes - chemistry ; Multienzyme Complexes - isolation & purification ; Polypeptides ; Primase ; Priming ; Proteins ; Replication ; RNA polymerase ; Synthesis ; Time Factors ; Yeast ; Yeasts
Is Part Of: Nature (London), 2022-06, Vol.606 (7912), p.204-210
Description: Chromosome replication is performed by a complex and intricate ensemble of proteins termed the replisome, where the DNA polymerases Polδ and Polε, DNA polymerase α-primase (Polα) and accessory proteins including AND-1, CLASPIN and TIMELESS-TIPIN (respectively known as Ctf4, Mrc1 and Tof1-Csm3 in Saccharomyces cerevisiae) are organized around the CDC45-MCM-GINS (CMG) replicative helicase . Because a functional human replisome has not been reconstituted from purified proteins, how these factors contribute to human DNA replication and whether additional proteins are required for optimal DNA synthesis are poorly understood. Here we report the biochemical reconstitution of human replisomes that perform fast and efficient DNA replication using 11 purified human replication factors made from 43 polypeptides. Polε, but not Polδ, is crucial for optimal leading-strand synthesis. Unexpectedly, Polε-mediated leading-strand replication is highly dependent on the sliding-clamp processivity factor PCNA and the alternative clamp loader complex CTF18-RFC. We show how CLASPIN and TIMELESS-TIPIN contribute to replisome progression and demonstrate that, in contrast to the budding yeast replisome , AND-1 directly augments leading-strand replication. Moreover, although AND-1 binds to Polα , the interaction is dispensable for lagging-strand replication, indicating that Polα is functionally recruited via an AND-1-independent mechanism for priming in the human replisome. Collectively, our work reveals how the human replisome achieves fast and efficient leading-strand and lagging-strand DNA replication, and provides a powerful system for future studies of the human replisome and its interactions with other DNA metabolic processes.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 0028-0836
EISSN: 1476-4687
DOI: 10.1038/s41586-022-04759-1
PMID: 35585232
Source: ProQuest One Psychology
MEDLINE
ProQuest Central

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Fast and efficient DNA replication with purified human proteins

2022. The Author(s), under exclusive licence to Springer Nature Limited. ;Copyright Nature Publishing Group Jun 2, 2022 ;ISSN: 0028-0836 ;EISSN: 1476-4687 ;DOI: 10.1038/s41586-022-04759-1 ;PMID: 35585232

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