The PCNA–Pol δ complex couples lagging strand DNA synthesis to parental histone transfer for epigenetic inheritance DOI Creative Commons
Albert Serra‐Cardona, Xu Hua, Seth McNutt

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(23)

Published: June 5, 2024

Inheritance of epigenetic information is critical for maintaining cell identity. The transfer parental histone H3-H4 tetramers, the primary carrier modifications on proteins, represents a crucial yet poorly understood step in inheritance information. Here, we show lagging strand DNA polymerase, Pol δ, interacts directly with and that interaction between δ sliding clamp PCNA regulates to strands, most likely independent their roles synthesis. When combined, mutations at Mcm2 compromise result greater reduction nucleosome occupancy nascent chromatin than either alone. Last, contributes positioning chromatin. On basis these results, suggest PCNA–Pol complex couples synthesis transfer, facilitating inheritance.

Language: Английский

Organization of Chromosomal DNA by SMC Complexes DOI Creative Commons
Stanislau Yatskevich, James Rhodes, Kim Nasmyth

et al.

Annual Review of Genetics, Journal Year: 2019, Volume and Issue: 53(1), P. 445 - 482

Published: Oct. 2, 2019

Structural maintenance of chromosomes (SMC) complexes are key organizers chromosome architecture in all kingdoms life. Despite seemingly divergent functions, such as segregation, maintenance, sister chromatid cohesion, and mitotic compaction, it appears that these function via highly conserved mechanisms they represent a novel class DNA translocases.

Language: Английский

Citations

319
Chromatin replication and epigenetic cell memory DOI
Kathleen R. Stewart-Morgan, Nataliya Petryk, Anja Groth

et al.

Nature Cell Biology, Journal Year: 2020, Volume and Issue: 22(4), P. 361 - 371

Published: March 30, 2020

Language: Английский

Citations

243
The Initiation of Eukaryotic DNA Replication DOI Open Access
Alessandro Costa, John F.X. Diffley

Annual Review of Biochemistry, Journal Year: 2022, Volume and Issue: 91(1), P. 107 - 131

Published: March 23, 2022

DNA replication in eukaryotic cells initiates from large numbers of sites called origins. Initiation these origins must be tightly controlled to ensure the entire genome is precisely duplicated each cell cycle. This accomplished through regulation first two steps replication: loading and activation replicative helicase. Here we describe what known about mechanism reactions a genetic, biochemical, structural perspective, focusing on recent progress using proteins budding yeast.

Language: Английский

Citations

179
Cryo-EM Structure of the Fork Protection Complex Bound to CMG at a Replication Fork DOI Creative Commons
Domagoj Baretić, Michael Jenkyn-Bedford,

Valentina Aria

et al.

Molecular Cell, Journal Year: 2020, Volume and Issue: 78(5), P. 926 - 940.e13

Published: May 4, 2020

The eukaryotic replisome, organized around the Cdc45-MCM-GINS (CMG) helicase, orchestrates chromosome replication. Multiple factors associate directly with CMG, including Ctf4 and heterotrimeric fork protection complex (Csm3/Tof1 Mrc1), which has important roles aiding normal replication rates stabilizing stalled forks. How these proteins interface CMG to execute functions is poorly understood. Here we present 3 3.5 Å resolution electron cryomicroscopy (cryo-EM) structures comprising Ctf4, at a fork. provide high-resolution views of CMG-DNA interactions, revealing mechanism for strand separation, show Csm3/Tof1 "grip" duplex DNA ahead via network interactions efficient pausing. Although Mrc1 was not resolved in our structures, determine its topology replisome by cross-linking mass spectrometry. Collectively, work reveals how four highly conserved components collaborate facilitate progression maintain genome stability.

Language: Английский

Citations

145
Recycling of modified H2A-H2B provides short-term memory of chromatin states DOI Creative Commons
Valentin Flury, Nazaret Reverón-Gómez, Nicolás Alcaraz

et al.

Cell, Journal Year: 2023, Volume and Issue: 186(5), P. 1050 - 1065.e19

Published: Feb. 6, 2023

Chromatin landscapes are disrupted during DNA replication and must be restored faithfully to maintain genome regulation cell identity. The histone H3-H4 modification landscape is by parental recycling of new histones. How impacts on H2A-H2B currently unknown. Here, we measure modifications H2A.Z across the cycle using quantitative genomics. We show that H2AK119ub1, H2BK120ub1, recycled accurately replication. Modified segregated symmetrically daughter strands via POLA1 lagging strand, but independent recycling. Post-replication, variant quickly restored, H2AK119ub1 guides accurate restoration H3K27me3. This work reveals epigenetic transmission identifies cross talk between in epigenome propagation. propose rapid short-term memory facilitates stable chromatin states.

Language: Английский

Citations

71
Symmetric inheritance of parental histones governs epigenome maintenance and embryonic stem cell identity DOI Creative Commons
Alice Wenger, Alva Biran, Nicolás Alcaraz

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(9), P. 1567 - 1578

Published: Sept. 1, 2023

Modified parental histones are segregated symmetrically to daughter DNA strands during replication and can be inherited through mitosis. How this may sustain the epigenome cell identity remains unknown. Here we show that transmission of histone-based information maintains fidelity embryonic stem plasticity. Asymmetric segregation H3-H4 in MCM2-2A mutants compromised mitotic inheritance histone modifications globally altered epigenome. This included widespread spurious deposition repressive modifications, suggesting elevated epigenetic noise. Moreover, H3K9me3 loss at repeats caused derepression H3K27me3 redistribution across bivalent promoters correlated with misexpression developmental genes. mutation challenged dynamic transitions cellular states cycle, enhancing naïve pluripotency reducing lineage priming G1. Furthermore, competence was diminished, correlating impaired exit from pluripotency. Collectively, argues a correctly balanced chromatin landscape able support mammalian differentiation.

Language: Английский

Citations

48
How Pol α-primase is targeted to replisomes to prime eukaryotic DNA replication DOI Creative Commons
Morgan Jones,

Valentina Aria,

Yasemin Baris

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 83(16), P. 2911 - 2924.e16

Published: July 27, 2023

During eukaryotic DNA replication, Pol α-primase generates primers at replication origins to start leading-strand synthesis and every few hundred nucleotides during discontinuous lagging-strand replication. How is targeted forks prime not fully understood. Here, by determining cryoelectron microscopy (cryo-EM) structures of budding yeast human replisomes containing α-primase, we reveal a conserved mechanism for the coordination priming replisome. binds directly leading edge CMG (CDC45-MCM-GINS) replicative helicase via complex interaction network. The non-catalytic PRIM2/Pri2 subunit forms two interfaces with that are critical in vitro cell growth. These interactions position primase catalytic PRIM1/Pri1 above exit channel template single-stranded (ssDNA), revealing why occurs efficiently only on elucidating overcome competition from RPA initiate primer synthesis.

Language: Английский

Citations

45
Parental histone transfer caught at the replication fork DOI
Ningning Li, Yuan Gao, Yujie Zhang

et al.

Nature, Journal Year: 2024, Volume and Issue: 627(8005), P. 890 - 897

Published: March 6, 2024

Language: Английский

Citations

35
The fork protection complex promotes parental histone recycling and epigenetic memory DOI Creative Commons
Sebastian Jespersen Charlton, Valentin Flury, Yutaka Kanoh

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(18), P. 5029 - 5047.e21

Published: Aug. 1, 2024

The inheritance of parental histones across the replication fork is thought to mediate epigenetic memory. Here, we reveal that fission yeast Mrc1 (CLASPIN in humans) binds H3-H4 tetramers and operates as a central coordinator symmetric histone inheritance. mutants key connector domain disrupted segregation lagging strand comparable Mcm2 histone-binding mutants. Both showed clonal asymmetric loss H3K9me-mediated gene silencing. AlphaFold predicted co-chaperoning by Mcm2, with bridging binding. Biochemical functional analysis validated this model revealed duality function: disabling binding lagging-strand recycling while another mutation impaired leading recycling. We propose toggles between pathways, part intra-replisome co-chaperoning, ensure transmission both daughter cells.

Language: Английский

Citations

19
Kinetics and mechanisms of mitotic inheritance of DNA methylation and their roles in aging-associated methylome deterioration DOI Open Access
Ming Xuan, Zhuqiang Zhang, Zhuoning Zou

et al.

Cell Research, Journal Year: 2020, Volume and Issue: 30(11), P. 980 - 996

Published: June 24, 2020

Language: Английский

Citations

121