Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

Shima, Naoko; Pederson, Kayla D.

doi:10.1016/j.dnarep.2017.06.019

Cited by 24 publications

(28 citation statements)

References 154 publications

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“…Under low dose of aphidicolin, the decrease in DNA replication fork velocity can be compensated by the firing of dormant origins, preventing under-replication (77)(78)(79)(80)(81)(82).…”

Section: Discussionmentioning

confidence: 99%

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

Courtot

Bournique

Maric

et al. 2020

Preprint

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DNA replication is very well orchestrated in mammalian cells due to a tight regulation of the temporal order of replication origin activation, known as the replication timing program. The replication timing of a given replication domain is very robust and well conserved in each cell type. Upon low replication stress, the slowing of replication forks induces delayed replication of some fragile regions leading to DNA damage and genetic instability. Except for these fragile regions, the direct impact of low replication stress on the replication timing in different cellular backgrounds has not been explored in detail. Here we analysed DNA replication timing across the whole genome in a panel of human cell lines in the presence of low replication stress. We demonstrate that low replication stress induced by aphidicolin has a stronger impact on the replication timing of cancer cells than non-tumour cells. Strikingly, we unveiled an enrichment of specific replication domains undergoing a switch from late to early replication in some cancer cells. We found that advances in replication timing correlate with heterochromatin regions poorly sensitive to DNA damage signalling while being subject to an increase of chromatin accessibility in response to aphidicolin. Finally, our data indicate that, following release from replication stress conditions, replication timing advances can be inherited by the next cellular generation, suggesting a new mechanism by which some cancer cells would adapt to cellular or environmental stress.

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“…Under low dose of aphidicolin, the decrease in DNA replication fork velocity can be compensated by the firing of dormant origins, preventing under-replication (77)(78)(79)(80)(81)(82).…”

Section: Discussionmentioning

confidence: 99%

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

Courtot

Bournique

Maric

et al. 2020

Preprint

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“…Taylor (1977) described how cells artificially held in S phase increased the number of DNA replication sites due to the activation of new origins. Years later, this concept could be integrated with the fact that more origins are 'licensed' by initiator proteins ORC, CDC6, CDT1 and MCM2-7 than those actually needed to duplicate the genome (reviewed by Alver et Shima and Pederson, 2017). Thus, many origins remain in a dormant state and are passively replicated by active forks in S phase.…”

Section: Introductionmentioning

confidence: 99%

Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins

Jodkowska

Pancaldi

Almeida

et al. 2019

Preprint

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share the first authorship; #R.A. and M.R. share the second authorship. ABSTRACTIn mammalian cells, chromosomal replication starts at thousands of origins at which replisomes are assembled and bidirectional DNA synthesis is established. The slowdown of DNA polymerases at endogenous or exogenous obstacles triggers the activation of additional 'dormant' origins whose genomic positions and regulation are not well understood. Here we report a comparative study of origin activity in mouse embryonic stem cells growing in control conditions or in the presence of mild replication stress. While stress-responsive origins can be identified, we find that the majority of them are also active, albeit with lower frequency, in the control population. To gain insights into the molecular and structural determinants of origin efficiency, we have analyzed the genetic and epigenetic features of origins stratified according to their frequency of activation. We have also integrated the linear origin maps into three-dimensional (3D) chromatin interaction networks, revealing a hierarchical organization in which clusters of connected origins are brought together by longer-range chromatin contacts. Origin efficiency is proportional to the number of connections established with other origin-containing fragments. Interacting origins tend to be activated with similar efficiency and share their timing of replication even when located in different topologically associated domains. Our results are consistent with a model in which clusters of origins are arranged in 3D in replication factories. Within each factory, 'main' and 'dormant' origins are functionally defined by a combination of chromatin environment and 3D connectivity.

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“…The high-resolution information about origin positions and functions available in budding yeast allowed us to show how such a mechanism was important for the normal distribution of origins across chromosomes. While the importance of origin distribution to genome stability has become clear, this is the first study to identify a specific chromatin-mediated mechanism that establishes the spatial distribution of MCM complexes across a eukaryotic genome (50; 51; 52).…”

Section: Discussionmentioning

confidence: 99%

Sir2 mitigates an intrinsic imbalance in origin licensing efficiency between early and late replicating euchromatin

Hoggard

Müller

Nieduszynski

et al. 2020

Preprint

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1A eukaryotic chromosome relies on the function of multiple spatially distributed DNA replication origins for its stable inheritance. 2 The location of an origin is determined by the chromosomal position of an MCM complex, the inactive form of the DNA 3 replicative helicase that is assembled on chromosomal DNA in G1-phase (a.k.a. origin licensing). While the biochemistry 4 of origin licensing is understood, the mechanisms that promote an adequate spatial distribution of MCM complexes across 5 chromosomes are not. We have elucidated a role for the Sir2 histone deacetylase in establishing the normal distribution of 6 MCM complexes across Saccharomyces cerevisiae chromosomes. In the absence of Sir2, MCM complexes accumulated within 7 both early-replicating euchromatin and telomeric heterochromatin, and replication activity within these regions was enhanced. 8 Concomitantly, the duplication of several regions of late-replicating euchromatin were delayed. Thus, Sir2-mediated attenuation 9 of origin licensing established the normal spatial distribution of origins across yeast chromosomes required for normal genome 10 duplication. 11Significance statement 12 In eukaryotes, multiple DNA replication origins, the sites where new DNA synthesis begins during the process 13 of cell division, must be adequately distributed across chromosomes to maintain normal cell proliferation 14 and genome stability. This study describes a repressive chromatin-mediated mechanism that acts at the 15 level of individual origins to attenuate the efficiency of origin formation. This attenuation is essential for 16 achieving the normal spatial distribution of origins across the chromosomes of the eukaryotic microbe Sac-17 charomyces cerevisiae. While the importance of chromosomal origin distribution to cellular fitness is now 18 widely acknowledged, this study is the first to define a specific chromatin modification that establishes the 19 normal spatial distribution of origins across a eukaryotic genome. 21An adequate distribution of DNA replication origins across eukaryotic chromosomes is important for 22 maintaining cell proliferation and genome stability over the course of multiple rounds of cell division. mosomal regions that contain a paucity of origins are linked to chromosome fragility and cancer-associated 24 deletions (1; 2; 3; 4). Origin function relies on two distinct cell-cycle restricted reactions (5). In G1-phase, 25 the ORC (origin recognition complex) and Cdc6 protein bind DNA and direct the assembly of a stable 26 catalytically inactive MCM (minichromosome maintenance) complex, a.k.a. origin licensing. In S-phase, 27 kinases and accessory proteins act on the MCM complex to convert it into two bidirectionally oriented 28 replicative helicases that unwind the DNA to allow for new DNA synthesis (a.k.a. origin activation). Thus, 29 the effective chromosomal distribution of two distinct reactions, MCM complex loading and MCM complex 30 activation, establishes the normal spatiotemporal distribution of orig...

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Dormant origins as a built-in safeguard in eukaryotic DNA replication against genome instability and disease development

Cited by 24 publications

References 154 publications

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

Low replication stress leads to specific replication timing advances associated to chromatin remodelling in cancer cells

Three-dimensional connectivity and chromatin environment mediate the activation efficiency of mammalian DNA replication origins

Sir2 mitigates an intrinsic imbalance in origin licensing efficiency between early and late replicating euchromatin

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