Histone H4K20 tri‐methylation at late‐firing origins ensures timely heterochromatin replication

Brustel, Julien; Kirstein, Nina; Izard, Fanny; Grimaud, Charlotte; Prorok, Paulina; Cayrou, Christelle; Schotta, Gunnar; Abdelsamie, Alhassan F; Déjardin, Jérôme; Méchali, Marcel; Baldacci, Giuseppe; Sardet, Claude; Cadoret, Jean‐Charles; Schepers, Aloys; Julien, Éric

doi:10.15252/embj.201796541

Cited by 63 publications

(84 citation statements)

References 62 publications

(150 reference statements)

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“…We show that H4K20me3 is present in a subset of non-genic late replicating initiation zones, which are enriched in ORC/ MCM binding. This confirms our previous finding that H4K20me3-mediated ORC-DNA binding enhances origin activity in certain environments 18, 32 . Finally, we find that the global density of ORC highly correlates with replication timing, an effect observed less prominently for MCM.…”

supporting

confidence: 92%

“…In multicellular organisms, replication initiates from flexible locations and no common consensus element for origin selection and activation has yet been identified. It is generally believed that chromatin features including histone modifications, nucleosome dynamics and DNA modifications contribute to origin specification 1, 16, 17 , including H4K20me3 that supports the licensing of a subset of late replicating origins in heterochromatin 18 . Thus, changing environmental conditions, DNA damage and the development status of each cell are integrated into highly dynamic local chromatin profiles, which influence the plasticity of origin selection 1 .…”

mentioning

confidence: 99%

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Active transcription regulates ORC/MCM distribution whereas replication timing correlates with ORC density in human cells

Kirstein¹,

Buschle²,

Wu³

et al. 2019

Preprint

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42Eukaryotic replication initiates during S phase from origins that have been licensed in 43 the preceding G1 phase. Here, we compare ChIP-seq profiles of the licensing factors 44Orc2, Orc3, Mcm3, and Mcm7 with replication initiation events obtained by Okazaki 45 fragment sequencing. We demonstrate that MCM is displaced from early replicating, 46 actively transcribed gene bodies, while ORC is mainly enriched at active TSS. Late 47Mammalian DNA replication is a highly orchestrated process ensuring the 55 exact inheritance of genomes of tens to thousands of million base pairs in size. In 56 human cells, replication initiates from 30,000 -50,000 replication origins per cell 1,2 . 57 Origins are not activated synchronously but are organized into individual replication 58 timing domains (RTDs), which replicate in a timely coordinated and reproducible 59 order from early to late in S phase 3,4 . The replication cascade or domino model 60 proposes that within one RTD, replication first initiates at the most efficient origins 61 and then spreads to less efficient origins. RTDs are separated by timing transition 62 regions and it is debated whether replication spreading is blocked at these regions 5,6 . 63The establishment of replication competence occurs in late mitosis and during 64 the G1 phase of the cell cycle 7 . The first step is the cell-cycle dependent assembly of 65 the evolutionary conserved origin recognition complex (ORC) to origins 8,9 . ORC and 66 two chaperones, Cdt1 and Cdc6, cooperatively load minichromosome maintenance 67 (MCM) complexes as double hexamers 10-12 . The MCM complex is the central unit of 68 the replicative helicase. The resulting multi-subunit complex is termed pre-replicative 69 complex (pre-RC). A single ORC loads multiple MCM helicases, which are 70 translocated from their original loading site, but no ORC, neither Cdc6, nor Cdt1 are 71 required for origin activation 13,14 . 72Replication origins are defined functionally. In the unicellular S. cerevisiae, 73 replication origins are genetically characterized by the ARS consensus sequence 15 . In 74 multicellular organisms, replication initiates from flexible locations and no common 75 consensus element for origin selection and activation has yet been identified. It is 76 generally believed that chromatin features including histone modifications, 77 nucleosome dynamics and DNA modifications contribute to origin specification 1,16,17 , 78 including H4K20me3 that supports the licensing of a subset of late replicating origins in heterochromatin 18 . Thus, changing environmental conditions, DNA damage and the 80 development status of each cell are integrated into highly dynamic local chromatin 81 profiles, which influence the plasticity of origin selection 1 . 82 Different approaches have been developed to characterize mammalian 83 replication initiation by single-molecule visualization (DNA combing) or sequencing 84 of purified initiation products (short nascent strands (SNS-seq), initiation site 85 sequencing (INI-seq) replicatio...

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supporting

confidence: 92%

mentioning

confidence: 99%

Active transcription regulates ORC/MCM distribution whereas replication timing correlates with ORC density in human cells

Kirstein¹,

Buschle²,

Wu³

et al. 2019

Preprint

Self Cite

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“…The monomethyltransferase SETD8 (also known as PR‐Set7) catalyzes H4K20me1. Depleting SETD8 causes defects in origin licensing, whereas inappropriate SETD8 expression in S phase promotes unregulated relicensing and rereplication . Subsequent trimethylation of histone H4K20, which requires H4K20me1 as a substrate, ensures that late‐firing origins are activated during S phase.…”

Section: G1: Preparing Dna For S Phasementioning

confidence: 99%

Preparation for DNA replication: the key to a successful S phase

Limas

Cook

2019

FEBS Letters

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Successful genome duplication is required for cell proliferation and demands extraordinary precision and accuracy. The mechanisms by which cells enter, progress through, and exit S phase are intense areas of focus in the cell cycle and genome stability fields. Key molecular events in the G1 phase of the cell division cycle, especially origin licensing, are essential for pre‐establishing conditions for efficient DNA replication during the subsequent S phase. If G1 events are poorly regulated or disordered, then DNA replication can be compromised leading to genome instability, a hallmark of tumorigenesis. Upon entry into S phase, coordinated origin firing and replication progression ensure complete, timely, and precise chromosome replication. Both G1 and S phase progressions are controlled by master cell cycle protein kinases and ubiquitin ligases that govern the activity and abundance of DNA replication factors. In this short review, we describe current understanding and recent developments related to G1 progression and S phase entrance and exit with a particular focus on origin licensing regulation in vertebrates.

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“…A recent study investigated the role of H4K20me marks in controlling late-firing origins. It showed that the conversion of K20me1 to K20me3 enhances ORCA recruitment and MCM loading at already defined origins required for the correct replication of heterochromatin (Brustel et al, 2017). Interestingly, the loss of Su4-20h, which is responsible for this methylation, delays RT for 15% of the mouse genome.…”

Section: Early Replicators Can Advance Replication Timing Locally In mentioning

confidence: 99%

Strong replicators associated with open chromatin are sufficient to establish an early replicating domain

Brossas

Chilaka

Counillon

et al. 2018

Preprint

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Vertebrate genomes replicate according to a precise temporal program strongly correlated with their organization into topologically associating domains. However, the molecular mechanisms underlying the establishment of early-replicating domains remain largely unknown. We defined two minimal cis-element modules containing a strong replication origin and chromatin modifier binding sites capable of shifting a targeted mid-late replicating region for earlier replication. When inserted side-by-side, these modules acted in cooperation, with similar effects on two late-replicating regions. Targeted insertions of these two modules at two chromosomal sites separated by 30 kb brought these two modules into close physical proximity and induced the formation of an early-replicating domain. Thus, combinations of strong origins and cis-elements capable of opening the chromatin structure are the basic units of early-replicating domains, and are absent from late-replicated regions. These findings are consistent with those of genomewide studies mapping strong initiation sites and open chromatin marks in vertebrate genomes.

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Histone H4K20 tri‐methylation at late‐firing origins ensures timely heterochromatin replication

Cited by 63 publications

References 62 publications

Active transcription regulates ORC/MCM distribution whereas replication timing correlates with ORC density in human cells

Active transcription regulates ORC/MCM distribution whereas replication timing correlates with ORC density in human cells

Preparation for DNA replication: the key to a successful S phase

Strong replicators associated with open chromatin are sufficient to establish an early replicating domain

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