Rescue from replication stress during mitosis

Fragkos, Michalis; Naim, Valeria

doi:10.1080/15384101.2017.1288322

Cited by 53 publications

(62 citation statements)

References 286 publications

(304 reference statements)

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“…In the presence of Chk1i, an additional accumulation of ssDNA could occur making RS more severe and thus leading to cell death . However, under some conditions, the combined deficiency of p53 with Chk1 abrogation could lead to mitotic catastrophe . The experiments of Wang et al .…”

Section: Discussionmentioning

confidence: 99%

Distinct cellular responses to replication stress leading to apoptosis or senescence

et al. 2019

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Replication stress ( RS ) is a major driver of genomic instability and tumorigenesis. Here, we investigated whether RS induced by the nucleotide analog fludarabine and specific kinase inhibitors [e.g. targeting checkpoint kinase 1 (Chk1) or ataxia telangiectasia and Rad3‐related ( ATR )] led to apoptosis or senescence in four cancer cell lines differing in TP 53 mutation status and expression of lamin A/C ( LA /C). RS resulted in uneven chromatin condensation in all cell types, as evidenced by the presence of metaphasic chromosomes with unrepaired DNA damage, as well as detection of less condensed chromatin in the same nucleus, frequent ultrafine anaphase bridges, and micronuclei. We observed that responses to these chromatin changes may be distinct in individual cell types, suggesting that expression of lamin A/C and lamin B1 ( LB 1) may play an important role in the transition of damaged cells to senescence. MCF 7 mammary carcinoma cells harboring wild‐type p53 (WT‐p53) and LA /C responded to RS by transition to senescence with a significant reduction of lamin B receptor and LB1 proteins. In contrast, a lymphoid cancer cell line WSU ‐ NHL (WT‐p53) lacking LA /C and expressing low levels of LB 1 died after several hours, while lines MEC ‐1 and SU ‐ DHL ‐4, both with mutated p53, and SU ‐ DHL ‐4 with mutations in LA /C, died at different rates by apoptosis. Our results show that, in addition to being influenced by p53 mutation status, the response to RS (apoptosis or senescence) may also be influenced by lamin A/C and LB 1 status.

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Section: Discussionmentioning

confidence: 99%

Distinct cellular responses to replication stress leading to apoptosis or senescence

et al. 2019

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“…The cells have developed several strategies, not mutually exclusive, to cope with replication stress. Notably, cells can accelerate the replication process by firing normally silent replication origins, extend S‐phase length, and continue DNA synthesis during the G2 phase and early mitosis . However, even if the replication process plays prolongations, CFSs tend to remain under‐replicated, a feature that elicited studies focusing on the replication dynamics along large genes hosting CFSs, but the mechanisms responsible for under‐replication are still unclear.…”

Section: Introductionmentioning

confidence: 99%

“…Notably, cells can accelerate the replication process by firing normally silent replication origins, 5 extend S-phase length, and continue DNA synthesis during the G2 phase and early mitosis. 15 However, even if the replication process plays prolongations, CFSs tend to remain underreplicated, a feature that elicited studies focusing on the replication dynamics along large genes hosting CFSs, 11,16 but the mechanisms responsible for under-replication are still unclear. Whatever the answer to this question, stresses that result in replication fork slowing or stalling undoubtedly enhance CFS breakage.…”

Section: Introductionmentioning

confidence: 99%

A journey with common fragile sites: From S phase to telophase

Debatisse

Rosselli

2018

Genes Chromosomes & Cancer

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Some regions of the genome, notably common fragile sites (CFSs), are hypersensitive to replication stress and often involved in the generation of gross chromosome rearrangements in cancer cells. CFSs nest within very large genes and display cell‐type‐dependent instability. Fragile or not, large genes tend to replicate late in S‐phase. A number of data now show that transcription perturbs replication completion across the body of large genes, particularly upon replication stress. However, the molecular mechanisms by which transcription elicits such under‐replication and subsequent instability remain unclear. We present here our view of the mechanisms responsible for CFS under‐replication and those allowing the cells to cope with this problem in G2 and mitosis. We notably focus on the major role played by the FANC proteins in the protection of CFSs from S phase up to late mitosis. We finally discuss a possible rationale for the conservation of large genes across vertebrate evolution.

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“…For example, variations in dNTP biosynthesis and ROS have been shown to directly modulate replisome architecture and replication fork velocity 55 . CFSs are late replicating, and slowing their replication further increases the risk of incomplete replication and breakage at the time of mitosis 6 . Furthermore, the timing of CFS replication is modulated by transcription 5 , and the failure to coordinate these two processes leads to CFS breakage 2 .…”

Section: Discussionmentioning

confidence: 99%

“…Notably, the transcription of very large genes encompassing CFSs can conflict with replication 2 and modify their replication dynamics 5 , leading to their incomplete replication when cells enter mitosis. Incomplete replication of CFSs leads to the persistence of late replication intermediates that are processed by structure-specific endonucleases, inducing mitotic defects and genomic instability if not properly resolved in a timely manner 6–8 . Despite their intrinsic instability, CFSs and their associated genes are conserved throughout evolution, hinting to a function of CFSs as sentinels of cellular stress 9, 10 .…”

Section: Introductionmentioning

confidence: 99%

FANCD2 tunes the UPR preventing mitochondrial stress-induced common fragile site instability

Fernandes

Miotto

Saint‐Ruf

et al. 2019

Preprint

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38Common fragile sites (CFSs) are genomic regions frequently involved in cancer-associated 39 rearrangements. Most CFSs lie within large genes, and their instability relies on 40 transcription-and replication-dependent mechanisms. Here, we uncover a role for the 41 UBL5-dependent branch of the unfolded protein response pathway (UPR) in the 42 maintenance of CFS stability. We show that genetic or pharmacological UPR activation 43 induces CFS gene expression and concomitant relocalization of FANCD2, a master 44 regulator of CFS stability, to CFSs. Furthermore, a genomic analysis of FANCD2 binding 45 sites identified an enrichment for mitochondrial UPR transcriptional response elements in 46 FANCD2 bound regions. We demonstrated that depletion of FANCD2 increases CFS gene 47 transcription and their instability while also inducing mitochondrial dysfunction and triggering 48 the activation of the UPR pathway. Depletion of UBL5, a mediator of the UPR, but not ATF4, 49reduces CFS gene expression and breakage in FANCD2-depleted cells. We thus 50 demonstrate that FANCD2 recruitment and function at CFSs depends on transcription and 51 UPR signaling, and in absence of transcription or UBL5, FANCD2 is dispensable for CFS 52 stability. We propose that FANCD2 coordinates nuclear and mitochondrial activities by 53 tuning the UPR to prevent genome instability. 54 55 56 57 58 CFS gene transcription and rescues chromosome fragility. Conversely, genetic or 127 pharmacological activation of the UPR induces CFS gene transcription and FANCD2 128 relocalization to CFS genes, dampening the UPR and preventing CFS instability. FANCD2 129 binding to CFS is dependent on CFS gene transcription and increases in a dose-dependent 130 manner. In addition, we show that FANCD2 is dispensable for maintaining CFS stability in 131 the absence of transcription. Mechanistically, we demonstrate that the UPR-dependent 132 induction of CFS genes is mediated by Ubiquitin-Like Protein 5 (UBL5), which was 133 previously shown to be involved in mitochondrial UPR signaling in C. elegans, and that 134 breaking up this signaling partially restores chromosome stability. We propose that CFSs 135 are part of a metabolic checkpoint, and by tuning the UPR with CFS replication, FANCD2 136 promotes metabolic homeostasis and genome integrity. 137 138 Results 140mRNA expression ATF4

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Rescue from replication stress during mitosis

Cited by 53 publications

References 286 publications

Distinct cellular responses to replication stress leading to apoptosis or senescence

Distinct cellular responses to replication stress leading to apoptosis or senescence

A journey with common fragile sites: From S phase to telophase

FANCD2 tunes the UPR preventing mitochondrial stress-induced common fragile site instability

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Rescue from replication stress during mitosis

Cited by 53 publications

References 286 publications

Distinct cellular responses to replication stress leading to apoptosis or senescence

Distinct cellular responses to replication stress leading to apoptosis or senescence

A journey with common fragile sites: From S phase to telophase

FANCD2 tunes the UPR preventing mitochondrial stress-­induced common fragile site instability

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FANCD2 tunes the UPR preventing mitochondrial stress-induced common fragile site instability