General and specific replication profiles are detected in normal human cells by genome-wide and single-locus molecular combing

Palumbo, Elisa; Tosoni, Elena; Russo, Antonella

doi:10.1016/j.yexcr.2013.10.001

Cited by 11 publications

(31 citation statements)

References 31 publications

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“…falciparum . A similar correlation between fork velocity and IOD was previously described for lymphoblastoid cells, fibroblasts and trypanosomatids 27, 45 , suggesting that fork velocity and IOD are commonly co-regulated. Indeed, in Chinese hamster cells it has been demonstrated that a slowing of replication forks can trigger the recruitment of latent origins within minutes, allowing the completion of S-phase in the same overall time period 44 .…”

Section: Discussionsupporting

confidence: 82%

Single-molecule analysis reveals that DNA replication dynamics vary across the course of schizogony in the malaria parasite Plasmodium falciparum

Stanojčić

Kuk

Ullah

et al. 2017

Sci Rep

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The mechanics of DNA replication and cell cycling are well-characterized in model organisms, but less is known about these basic aspects of cell biology in early-diverging Apicomplexan parasites, which do not divide by canonical binary fission but undergo unconventional cycles. Schizogony in the malaria parasite, Plasmodium, generates ~16–24 new nuclei via independent, asynchronous rounds of genome replication prior to cytokinesis and little is known about the control of DNA replication that facilitates this. We have characterised replication dynamics in P. falciparum throughout schizogony, using DNA fibre labelling and combing to visualise replication forks at a single-molecule level. We show that origins are very closely spaced in Plasmodium compared to most model systems, and that replication dynamics vary across the course of schizogony, from faster synthesis rates and more widely-spaced origins through to slower synthesis rates and closer-spaced origins. This is the opposite of the pattern usually seen across S-phase in human cells, when a single genome is replicated. Replication forks also appear to stall at an unusually high rate throughout schizogony. Our work explores Plasmodium DNA replication in unprecedented detail and opens up tremendous scope for analysing cell cycle dynamics and developing interventions targetting this unique aspect of malaria biology.

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Section: Discussionsupporting

confidence: 82%

Single-molecule analysis reveals that DNA replication dynamics vary across the course of schizogony in the malaria parasite Plasmodium falciparum

Stanojčić

Kuk

Ullah

et al. 2017

Sci Rep

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“…As our data suggest that dynamic events occur at FHIT during normal cell proliferation, we supposed that the abnormal sequences might be somehow related to the CNVs described by Glover et al In agreement with their hypothesis, we found that sequence rearrangements at FHIT might be generated during DNA replication by pathways contributing to the restart of stalled/collapsed forks . The diverse proportions recorded for sequence changes in different cell types might be related to the existence of specific replication programs; this observation provides further evidence that the analysis of a comprehensive panel of cell types is recommended to better understand in‐depth mechanisms and events characterizing CFS instability.…”

Section: Cfs Instability In Nontumor Cells: State Of the Artsupporting

confidence: 89%

“…Consequently, impairment of replication fork progression and fork collapse may occur, which may finally lead to chromosomal breakage . Moreover, several human CFSs harbor very large genes, spanning 800 kb ‐ 2 Mb, and are characterized by late replication timing . These features led to the early hypotheses that CFS fragility may depend on slowed/impaired DNA replication, which in turn may cause single‐strand DNA persistence until G2/M, as well as abnormal chromatin condensation .…”

Section: Introductionmentioning

confidence: 99%

“…These features led to the early hypotheses that CFS fragility may depend on slowed/impaired DNA replication, which in turn may cause single‐strand DNA persistence until G2/M, as well as abnormal chromatin condensation . However, recent evidence demonstrates that replication dynamics at CFSs does not imply extensive fork slowing/stalling; instead, peculiar patterns of replication origin activation (paucity of origins, transition zones between early/late activated origins) may lead to CFS instability . In the case of FRA3B , which is the most active CFS in human lymphocytes, only the combination of late replication and paucity of initiation events sets the conditions necessary to the expression of the fragility; this pattern is moreover cell specific .…”

Section: Introductionmentioning

confidence: 99%

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Common fragile site instability in normal cells: Lessons and perspectives

Palumbo

Russo

2018

Genes Chromosomes & Cancer

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Mechanisms and events related to common fragile site (CFS) instability are well known in cancer cells. Here, we argue that normal cells remain an important experimental model to address questions related to CFS instability in the absence of alterations in cell cycle and DNA damage repair pathways, which are common features acquired in cancer. Furthermore, a major gap of knowledge concerns the stability of CFSs during gametogenesis. CFS instability in meiotic or postmeiotic stages of the germ cell line could generate chromosome deletions or large rearrangements. This in turn can lead to the functional loss of the several CFS‐associated genes with tumor suppressor function. Our hypothesis is that such mutations can potentially result in genetic predisposition to develop cancer. Indirect evidence for CFS instability in human germ cells has been provided by genomic investigations in family pedigrees associated with genetic disease. The issue of CFS instability in the germ cell line should represent one of the future efforts, and may take advantage of the existence of sequence and functional conservation of CFSs between rodents and humans.

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“…[41][42][43] Briefly, genome-wide replication analysis was carried out by IdU and CldU immunodetection, and the integrity of the DNA molecules was assessed by an anti-ssDNA antibody. When cells were exposed to replication stress (0.4 µM APH for 2 hours), labeling was performed during the last hour of APH treatment.…”

Section: Dna Replication Analysismentioning

confidence: 99%

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

et al. 2019

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In mammalian cells, the catabolic activity of the dNTP triphosphohydrolase SAMHD1 sets the balance and concentration of the four dNTPs. Deficiency of SAMHD1 leads to unequally increased pools and marked dNTP imbalance. Imbalanced dNTP pools increase mutation frequency in cancer cells, but it is not known if the SAMHD1induced dNTP imbalance favors accumulation of somatic mutations in nontransformed cells. Here, we have investigated how fibroblasts from Aicardi-Goutières Syndrome (AGS) patients with mutated SAMHD1 react to the constitutive pool imbalance characterized by a huge dGTP pool. We focused on the effects on dNTP pools, cell cycle progression, dynamics and fidelity of DNA replication, and efficiency of UV-induced DNA repair. AGS fibroblasts entered senescence prematurely or upregulated genes involved in G1/S transition and DNA replication. The normally growing AGS cells exhibited unchanged DNA replication dynamics and, when quiescent, faster rate of excision repair of UV-induced DNA damages. To investigate whether the lack of SAMHD1 affects DNA replication fidelity, we compared de novo mutations in AGS and WT cells by exome next-generation sequencing. Somatic variant analysis indicated a mutator phenotype suggesting that SAMHD1 is a caretaker gene whose deficiency is per se mutagenic, promoting genome instability in nontransformed cells.

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General and specific replication profiles are detected in normal human cells by genome-wide and single-locus molecular combing

Cited by 11 publications

References 31 publications

Single-molecule analysis reveals that DNA replication dynamics vary across the course of schizogony in the malaria parasite Plasmodium falciparum

Single-molecule analysis reveals that DNA replication dynamics vary across the course of schizogony in the malaria parasite Plasmodium falciparum

Common fragile site instability in normal cells: Lessons and perspectives

SAMHD1‐deficient fibroblasts from Aicardi‐Goutières Syndrome patients can escape senescence and accumulate mutations

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