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Article ; Online: Author's overview: identifying SARS-CoV-2 antiviral compounds.

Diffley, John F X

2021 Volume 478, Issue 13, Page(s) 2533–2535

Abstract: In response to the COVID-19 pandemic, we began a project in March 2020 to identify small molecule inhibitors of SARS-CoV-2 enzymes from a library of chemical compounds containing many established pharmaceuticals. Our hope was that inhibitors we found ... ...

Abstract	In response to the COVID-19 pandemic, we began a project in March 2020 to identify small molecule inhibitors of SARS-CoV-2 enzymes from a library of chemical compounds containing many established pharmaceuticals. Our hope was that inhibitors we found might slow the replication of the SARS-CoV-2 virus in cells and ultimately be useful in the treatment of COVID-19. The seven accompanying manuscripts describe the results of these chemical screens. This overview summarises the main highlights from these screens and discusses the implications of our results and how our results might be exploited in future.
MeSH term(s)	Animals ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Drug Evaluation, Preclinical ; Enzyme Assays ; Humans ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/metabolism
Chemical Substances	Antiviral Agents ; Small Molecule Libraries ; Viral Nonstructural Proteins
Language	English
Publishing date	2021-07-01
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2969-5
ISSN	1470-8728 ; 0006-2936 ; 0306-3275 ; 0264-6021
ISSN (online)	1470-8728
ISSN	0006-2936 ; 0306-3275 ; 0264-6021
DOI	10.1042/BCJ20210426
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Article ; Online: The Initiation of Eukaryotic DNA Replication.

Costa, Alessandro / Diffley, John F X

Annual review of biochemistry

2022 Volume 91, Page(s) 107–131

Abstract: DNA replication in eukaryotic cells initiates from large numbers of sites called replication origins. Initiation of replication from these origins must be tightly controlled to ensure the entire genome is precisely duplicated in each cell cycle. This is ... ...

Abstract	DNA replication in eukaryotic cells initiates from large numbers of sites called replication origins. Initiation of replication from these origins must be tightly controlled to ensure the entire genome is precisely duplicated in each cell cycle. This is accomplished through the regulation of the first two steps in replication: loading and activation of the replicative DNA helicase. Here we describe what is known about the mechanism and regulation of these two reactions from a genetic, biochemical, and structural perspective, focusing on recent progress using proteins from budding yeast.
MeSH term(s)	Cell Cycle/genetics ; DNA Replication ; Eukaryota/genetics ; Eukaryotic Cells/metabolism ; Replication Origin
Language	English
Publishing date	2022-03-23
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	207924-0
ISSN	1545-4509 ; 0066-4154
ISSN (online)	1545-4509
ISSN	0066-4154
DOI	10.1146/annurev-biochem-072321-110228
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Article ; Online: Unchecked nick ligation can promote localized genome re-replication.

Johansson, Erik / Diffley, John F X

Current biology : CB

2021 Volume 31, Issue 11, Page(s) R710–R711

Abstract: Single-stranded DNA breaks, or nicks, are amongst the most common forms of DNA damage in cells. They can be repaired by ligation; however, if a nick occurs just ahead of an approaching replisome, the outcome is a collapsed replication fork comprising a ... ...

Abstract	Single-stranded DNA breaks, or nicks, are amongst the most common forms of DNA damage in cells. They can be repaired by ligation; however, if a nick occurs just ahead of an approaching replisome, the outcome is a collapsed replication fork comprising a single-ended double-strand break and a 'hybrid nick' with parental DNA on one side and nascent DNA on the other (Figure 1A). We realized that in eukaryotic cells, where replication initiates from multiple replication origins, a fork from an adjacent origin can promote localized re-replication if the hybrid nick is ligated. We have modelled this situation with purified proteins in vitro and have found that there is, indeed, an additional hazard that eukaryotic replisomes face. We discuss how this problem might be mitigated.
MeSH term(s)	DNA/biosynthesis ; DNA/metabolism ; DNA Breaks, Double-Stranded ; DNA Breaks, Single-Stranded ; DNA Ligases/metabolism ; DNA Replication ; DNA-Directed DNA Polymerase/metabolism ; Escherichia coli/enzymology ; Escherichia coli/genetics ; Genome/genetics ; Multienzyme Complexes/metabolism ; Replication Origin ; Yeasts/enzymology ; Yeasts/genetics
Chemical Substances	Multienzyme Complexes ; DNA (9007-49-2) ; DNA synthesome (EC 2.7.7.-) ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; DNA Ligases (EC 6.5.1.-)
Language	English
Publishing date	2021-06-08
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2021.03.043
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Zs.A 3208: Show issues

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Article ; Online: Cyclin E-induced replicative stress drives p53-dependent whole-genome duplication.

Zeng, Jingkun / Hills, Stephanie A / Ozono, Eiko / Diffley, John F X

Cell

2023 Volume 186, Issue 3, Page(s) 528–542.e14

Abstract: Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, ...

Abstract	Whole-genome duplication (WGD) is a frequent event in cancer evolution and an important driver of aneuploidy. The role of the p53 tumor suppressor in WGD has been enigmatic: p53 can block the proliferation of tetraploid cells, acting as a barrier to WGD, but can also promote mitotic bypass, a key step in WGD via endoreduplication. In wild-type (WT) p53 tumors, WGD is frequently associated with activation of the E2F pathway, especially amplification of CCNE1, encoding cyclin E1. Here, we show that elevated cyclin E1 expression causes replicative stress, which activates ATR- and Chk1-dependent G2 phase arrest. p53, via its downstream target p21, together with Wee1, then inhibits mitotic cyclin-dependent kinase activity sufficiently to activate APC/C
MeSH term(s)	Humans ; Cell Line, Tumor ; Cyclin E/genetics ; Cyclin E/metabolism ; Cyclin-Dependent Kinase Inhibitor p21/genetics ; Gene Duplication ; Mitosis ; Neoplasms/genetics ; Neoplasms/pathology ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Cyclin E ; Cyclin-Dependent Kinase Inhibitor p21 ; Tumor Suppressor Protein p53 ; CCNE1 protein, human ; TP53 protein, human
Language	English
Publishing date	2023-01-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2022.12.036
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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Article ; Online: A replication fork determinant for the establishment of sister chromatid cohesion.

Minamino, Masashi / Bouchoux, Céline / Canal, Berta / Diffley, John F X / Uhlmann, Frank

Cell

2023 Volume 186, Issue 4, Page(s) 837–849.e11

Abstract: Concomitant with DNA replication, the chromosomal cohesin complex establishes cohesion between newly replicated sister chromatids. Cohesion establishment requires acetylation of conserved cohesin lysine residues by Eco1 acetyltransferase. Here, we ... ...

Abstract	Concomitant with DNA replication, the chromosomal cohesin complex establishes cohesion between newly replicated sister chromatids. Cohesion establishment requires acetylation of conserved cohesin lysine residues by Eco1 acetyltransferase. Here, we explore how cohesin acetylation is linked to DNA replication. Biochemical reconstitution of replication-coupled cohesin acetylation reveals that transient DNA structures, which form during DNA replication, control the acetylation reaction. As polymerases complete lagging strand replication, strand displacement synthesis produces DNA flaps that are trimmed to result in nicked double-stranded DNA. Both flaps and nicks stimulate cohesin acetylation, while subsequent nick ligation to complete Okazaki fragment maturation terminates the acetylation reaction. A flapped or nicked DNA substrate constitutes a transient molecular clue that directs cohesin acetylation to a window behind the replication fork, next to where cohesin likely entraps both sister chromatids. Our results provide an explanation for how DNA replication is linked to sister chromatid cohesion establishment.
MeSH term(s)	Chromatids/metabolism ; Nuclear Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; DNA Replication ; Cell Cycle Proteins/genetics ; Cell Cycle Proteins/metabolism ; DNA ; Acetyltransferases/genetics ; Acetyltransferases/metabolism
Chemical Substances	Nuclear Proteins ; Saccharomyces cerevisiae Proteins ; Cell Cycle Proteins ; DNA (9007-49-2) ; Acetyltransferases (EC 2.3.1.-) ; ECO1 protein, S cerevisiae (EC 2.3.1.-)
Language	English
Publishing date	2023-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2022.12.044
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Zs.A 1167: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 58: Show issues

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Article ; Online: Eukaryotic DNA replication with purified budding yeast proteins.

Posse, Viktor / Johansson, Erik / Diffley, John F X

Methods in enzymology

2021 Volume 661, Page(s) 1–33

Abstract: The in vitro reconstitution of origin firing was a key step toward the biochemical reconstitution of eukaryotic DNA replication in budding yeast. Today the basic replication assay involves proteins purified from 24 separate protocols that have evolved ... ...

Abstract	The in vitro reconstitution of origin firing was a key step toward the biochemical reconstitution of eukaryotic DNA replication in budding yeast. Today the basic replication assay involves proteins purified from 24 separate protocols that have evolved since their first publication, and as a result, the efficiency and reliability of the in vitro replication system has improved. Here we will present protocols for all 24 purifications together with a general protocol for the in vitro replication assay and some tips for troubleshooting problems with the assay.
MeSH term(s)	DNA Replication ; DNA, Fungal/genetics ; DNA, Fungal/metabolism ; Fungal Proteins/metabolism ; Replication Origin ; Reproducibility of Results ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomycetales/genetics ; Saccharomycetales/metabolism
Chemical Substances	DNA, Fungal ; Fungal Proteins ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2021-10-22
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1557-7988
ISSN (online)	1557-7988
DOI	10.1016/bs.mie.2021.08.018
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Article ; Online: A DNA replication fork-centric view of the budding yeast DNA damage response.

McClure, Allison W / Canal, Berta / Diffley, John F X

DNA repair

2022 Volume 119, Page(s) 103393

Abstract: The DNA damage response (DDR) checkpoint is activated when DNA is damaged or when DNA replication forks stall. The DDR checkpoint plays a critical role in preserving the integrity of stalled replication forks; this is essential for subsequent fork ... ...

Abstract	The DNA damage response (DDR) checkpoint is activated when DNA is damaged or when DNA replication forks stall. The DDR checkpoint plays a critical role in preserving the integrity of stalled replication forks; this is essential for subsequent fork resumption, faithful and complete genome replication, and cell survival. The mechanisms by which the DDR checkpoint preserves stalled replication forks are still incompletely understood. Many substrates of the DDR checkpoint kinases have been identified over the years, but in many cases the functional consequences of phosphorylation are still unclear. Emerging as a complementary approach, recent advances in biochemical reconstitution of DNA replication have made it possible to characterise specific mechanisms of DNA replication regulation by the DDR checkpoint. In this review, we discuss the role of DNA replication in the activation of the DDR checkpoint and how this checkpoint regulates different aspects of DNA replication. We then distinguish between checkpoint action locally at the site of replication stalling and more globally, and we discuss how these functions contribute to coordinating complete replication of the genome in the face of replication stress.
MeSH term(s)	Cell Cycle Checkpoints ; DNA ; DNA Damage ; DNA Replication ; Saccharomycetales/genetics
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2022-08-30
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2071608-4
ISSN	1568-7856 ; 1568-7864
ISSN (online)	1568-7856
ISSN	1568-7864
DOI	10.1016/j.dnarep.2022.103393
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Zs.A 5555: Show issues

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Article ; Online: Budding yeast Rap1, but not telomeric DNA, is inhibitory for multiple stages of DNA replication in vitro.

Douglas, Max E / Diffley, John F X

Nucleic acids research

2021 Volume 49, Issue 10, Page(s) 5671–5683

Abstract: Telomeres are copied and reassembled each cell division cycle through a multistep process called telomere replication. Most telomeric DNA is duplicated semiconservatively during this process, but replication forks frequently pause or stall at telomeres ... ...

Abstract	Telomeres are copied and reassembled each cell division cycle through a multistep process called telomere replication. Most telomeric DNA is duplicated semiconservatively during this process, but replication forks frequently pause or stall at telomeres in yeast, mouse and human cells, potentially causing chronic telomere shortening or loss in a single cell cycle. We have investigated the cause of this effect by examining the replication of telomeric templates in vitro. Using a reconstituted assay for eukaryotic DNA replication in which a complete eukaryotic replisome is assembled and activated with purified proteins, we show that budding yeast telomeric DNA is efficiently duplicated in vitro unless the telomere binding protein Rap1 is present. Rap1 acts as a roadblock that prevents replisome progression and leading strand synthesis, but also potently inhibits lagging strand telomere replication behind the fork. Both defects can be mitigated by the Pif1 helicase. Our results suggest that GC-rich sequences do not inhibit DNA replication per se, and that in the absence of accessory factors, telomere binding proteins can inhibit multiple, distinct steps in the replication process.
MeSH term(s)	Base Composition/genetics ; DNA Helicases/genetics ; DNA Helicases/metabolism ; DNA Replication/genetics ; Gene Expression ; In Vitro Techniques ; Recombinant Proteins ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Saccharomycetales/genetics ; Saccharomycetales/metabolism ; Shelterin Complex ; Telomere/genetics ; Telomere/metabolism ; Telomere-Binding Proteins/genetics ; Telomere-Binding Proteins/metabolism ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	RAP1 protein, S cerevisiae ; Recombinant Proteins ; Saccharomyces cerevisiae Proteins ; Shelterin Complex ; Telomere-Binding Proteins ; Transcription Factors ; PIF1 protein, S cerevisiae (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2021-06-17
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkab416
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Zs.A 1067: Show issues

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Article ; Online: On the road to replication.

Diffley, John F X

EMBO molecular medicine

2016 Volume 8, Issue 2, Page(s) 77–79

MeSH term(s)	Cell Cycle ; DNA Replication ; Genomic Instability ; Multienzyme Complexes/isolation & purification ; Multienzyme Complexes/metabolism
Chemical Substances	Multienzyme Complexes
Language	English
Publishing date	2016-01-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.201505965
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Zs.A 6784: Show issues

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Article ; Online: A chromatinized origin reduces the mobility of ORC and MCM through interactions and spatial constraint.

Sánchez, Humberto / Liu, Zhaowei / van Veen, Edo / van Laar, Theo / Diffley, John F X / Dekker, Nynke H

Nature communications

2023 Volume 14, Issue 1, Page(s) 6735

Abstract: Chromatin replication involves the assembly and activity of the replisome within the nucleosomal landscape. At the core of the replisome is the Mcm2-7 complex (MCM), which is loaded onto DNA after binding to the Origin Recognition Complex (ORC). In yeast, ...

Abstract	Chromatin replication involves the assembly and activity of the replisome within the nucleosomal landscape. At the core of the replisome is the Mcm2-7 complex (MCM), which is loaded onto DNA after binding to the Origin Recognition Complex (ORC). In yeast, ORC is a dynamic protein that diffuses rapidly along DNA, unless halted by origin recognition sequences. However, less is known about the dynamics of ORC proteins in the presence of nucleosomes and attendant consequences for MCM loading. To address this, we harnessed an in vitro single-molecule approach to interrogate a chromatinized origin of replication. We find that ORC binds the origin of replication with similar efficiency independently of whether the origin is chromatinized, despite ORC mobility being reduced by the presence of nucleosomes. Recruitment of MCM also proceeds efficiently on a chromatinized origin, but subsequent movement of MCM away from the origin is severely constrained. These findings suggest that chromatinized origins in yeast are essential for the local retention of MCM, which may facilitate subsequent assembly of the replisome.
MeSH term(s)	Origin Recognition Complex/genetics ; Origin Recognition Complex/metabolism ; Nucleosomes ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Cell Cycle Proteins/metabolism ; DNA/metabolism ; DNA Replication ; Minichromosome Maintenance Proteins/genetics ; Minichromosome Maintenance Proteins/metabolism ; Saccharomyces cerevisiae Proteins/genetics ; Saccharomyces cerevisiae Proteins/metabolism ; Replication Origin
Chemical Substances	Origin Recognition Complex ; Nucleosomes ; Cell Cycle Proteins ; DNA (9007-49-2) ; Minichromosome Maintenance Proteins (EC 3.6.4.12) ; Saccharomyces cerevisiae Proteins
Language	English
Publishing date	2023-10-23
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-42524-8
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