Under-Replicated DNA: The Byproduct of Large Genomes?

Bertolin, Agustina P.; Hoffmann, Jean-Sébastien; Gottifredi, Vanesa

doi:10.3390/cancers12102764

Cited by 23 publications

(26 citation statements)

References 134 publications

(282 reference statements)

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“…UFBs can be further processed in the following replication cycles. In contrast to bulky chromosome bridges, they may be involved in a pathway that promotes, rather than restrains, genomic stability [ 27 ]. UFBs are formed as a consequence of the accumulation of under-replicated DNA (UR-DNA) ( Figure 1 ).…”

Section: Cellular Phenotypes Associated With Cinmentioning

confidence: 99%

“…Intriguingly, UR-DNA accumulation at the end of S phase is potentially frequent in cells with large genomes. Such a phenomenon is potentiated by the accumulation of DNA replication barriers or other conditions such as nucleotide depletion [ 27 ]. There are DNA regions poor in replication origins that are more prone to under-replication, such as common fragile sites.…”

Section: Cellular Phenotypes Associated With Cinmentioning

confidence: 99%

“…The proper and timely activation of DDR mechanisms, such as DNA repair and DNA damage tolerance, is crucial to prevent CIN generated after replication stress. Even in optimal DNA repair conditions, the chances of replication forks running into DNA damage and other replication barriers are high, posing challenges to completing DNA replication [ 27 ]. Because replicative DNA polymerases are incapable of using damaged DNA bases as templates for DNA replication, they stall when encountering damaged DNA.…”

Section: The Role Of the Dna Damage Response In The Prevention Of Cinmentioning

confidence: 99%

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Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

Siri

Martino

Gottifredi

2021

Cancers

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Chromosomal instability (CIN) refers to an increased rate of acquisition of numerical and structural changes in chromosomes and is considered an enabling characteristic of tumors. Given its role as a facilitator of genomic changes, CIN is increasingly being considered as a possible therapeutic target, raising the question of which variables may convert CIN into an ally instead of an enemy during cancer treatment. This review discusses the origins of structural chromosome abnormalities and the cellular mechanisms that prevent and resolve them, as well as how different CIN phenotypes relate to each other. We discuss the possible fates of cells containing structural CIN, focusing on how a few cell duplication cycles suffice to induce profound CIN-mediated genome alterations. Because such alterations can promote tumor adaptation to treatment, we discuss currently proposed strategies to either avoid CIN or enhance CIN to a level that is no longer compatible with cell survival.

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Section: Cellular Phenotypes Associated With Cinmentioning

confidence: 99%

Section: Cellular Phenotypes Associated With Cinmentioning

confidence: 99%

Section: The Role Of the Dna Damage Response In The Prevention Of Cinmentioning

confidence: 99%

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Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

Siri

Martino

Gottifredi

2021

Cancers

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“…RS in cancers frequently results from the oncogenedriven perturbation of the replication initiation program (origin activation and timing) and increased conflicts between replication and transcription. This triggers the generation of under-replicated regions as well as the persistence of stalled and collapsed forks, major sources for chromosomal breakage and chromosome instability [137]. If two converging replication forks stall with no possible compensation by licensed origins in-between, a double fork-stalling event occurs leading to the generation of under-replicated parental DNA and causing chromosome breaks when the cells enter mitosis [137,138].…”

Section: Dna Replication Fork Arrest Replication Stress Checkpoint Activation and Genome Instability In Cancermentioning

confidence: 99%

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

Tomasini

Guecheva²,

Leguisamo³

et al. 2021

Cancers

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Despite the ample improvements of CRC molecular landscape, the therapeutic options still rely on conventional chemotherapy-based regimens for early disease, and few targeted agents are recommended for clinical use in the metastatic setting. Moreover, the impact of cytotoxic, targeted agents, and immunotherapy combinations in the metastatic scenario is not fully satisfactory, especially the outcomes for patients who develop resistance to these treatments need to be improved. Here, we examine the opportunity to consider therapeutic agents targeting DNA repair and DNA replication stress response as strategies to exploit genetic or functional defects in the DNA damage response (DDR) pathways through synthetic lethal mechanisms, still not explored in CRC. These include the multiple actors involved in the repair of DNA double-strand breaks (DSBs) through homologous recombination (HR), classical non-homologous end joining (NHEJ), and microhomology-mediated end-joining (MMEJ), inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP), as well as inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM). We also review the biomarkers that guide the use of these agents, and current clinical trials with targeted DDR therapies.

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“…This is facilitated by the excessive loading of prereplicative complexes (Pre-RCs) onto DNA that remain inactive unless RS happens, named 'dormant origins' [3]. However, if two converging replication forks are arrested with no dormant origin in between, a double fork stalling (DFS) event occurs with a serious probability of compromised replication and a generation of under-replicated parental DNA [4].…”

Section: Introductionmentioning

confidence: 99%

The Heritability of Replication Problems

Hoffmann¹

2021

Cells

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The major challenge of DNA replication is to provide daughter cells with intact and fully duplicated genetic material. However, various endogenous or environmental factors can slow down or stall DNA replication forks; these replication problems are known to fuel genomic instability and associated pathology, including cancer progression. Whereas the mechanisms emphasizing the source and the cellular responses of replicative problems have attracted much consideration over the past decade, the propagation through mitosis of genome modification and its heritability in daughter cells when the stress is not strong enough to provoke a checkpoint response in G2/M was much less documented. Some recent studies addressing whether low replication stress could impact the DNA replication program of the next generation of cells made the remarkable discovery that DNA damage can indeed be transmitted to daughter cells and can be processed in the subsequent S-phase, and that the replication timing program at a subset of chromosomal domains can also be impacted in the next generation of cells. Such a progression of replication problems into mitosis and daughter cells may appear counter-intuitive, but it could offer considerable advantages by alerting the next generation of cells of potentially risky loci and offering the possibility of an adaptive mechanism to anticipate a reiteration of problems, notably for cancer cells in the context of resistance to therapy.

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Under-Replicated DNA: The Byproduct of Large Genomes?

Cited by 23 publications

References 134 publications

Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

Structural Chromosome Instability: Types, Origins, Consequences, and Therapeutic Opportunities

Analyzing the Opportunities to Target DNA Double-Strand Breaks Repair and Replicative Stress Responses to Improve Therapeutic Index of Colorectal Cancer

The Heritability of Replication Problems

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