Challenges to DNA replication in hypoxic conditions

Ng, Natalie; Purshouse, Karin; Foskolou, Iosifina P.; Olcina, Monica M.; Hammond, Ester M.

doi:10.1111/febs.14377

Cited by 48 publications

(39 citation statements)

References 79 publications

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“…Replication stress is characterized by the presence of stalled forks with long stretches of ssDNA. 9 Replication Protein A is one of the initial responders to replication stress and binds to ssDNA for stabilization. Despite the replication stress, some cells can bypass genetic lesions and continue replicating by repriming the lesion.…”

Section: Discussionmentioning

confidence: 99%

“…8 In addition, severe hypoxia can lead to replication stress and can impact the efficient replication of the genome. 9 Longer periods of severe hypoxia lead to stalled replication forks which can then lead to over-replication of DNA. 9 In addition, reoxygenation during intermittent hypoxic conditions can lead to increased Reactive Oxygen Species (ROS) and ATP deprivation and can induce reprogramming in the DNA repair gene expression.…”

Section: Introductionmentioning

confidence: 99%

“…9 Longer periods of severe hypoxia lead to stalled replication forks which can then lead to over-replication of DNA. 9 In addition, reoxygenation during intermittent hypoxic conditions can lead to increased Reactive Oxygen Species (ROS) and ATP deprivation and can induce reprogramming in the DNA repair gene expression. 10 Further, increase in ROS is directly associated with increased DNA damages.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia increases mutational load of breast cancer cells through frameshift mutations

et al. 2020

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Tumor hypoxia-induced downregulation of DNA repair pathways and enhanced replication stress are potential sources of genomic instability. A plethora of genetic changes such as point mutations, large deletions and duplications, microsatellite and chromosomal instability have been discovered in cells under hypoxic stress. However, the influence of hypoxia on the mutational burden of the genome is not fully understood. Here, we attempted to elucidate the DNA damage response and repair patterns under different types of hypoxic stress. In addition, we examined the pattern of mutations exclusively induced under chronic and intermittent hypoxic conditions in two breast cancer cell lines using exome sequencing. Our data indicated that hypoxic stress resulted in transcriptional downregulation of DNA repair genes which can impact the DNA repair induced during anoxic as well as reoxygenated conditions. In addition, our findings demonstrate that hypoxic conditions increased the mutational burden, characterized by an increase in frameshift insertions and deletions. The somatic mutations were random and nonrecurring, as huge variations within the technical duplicates were recognized. Hypoxia also resulted in an increase in the formation of potential neoantigens in both cell lines. More importantly, these data indicate that hypoxic stress mitigates DNA damage repair pathways and causes an increase in the mutational burden of tumor cells, thereby interfering with hypoxic cancer cell immunogenicity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hypoxia increases mutational load of breast cancer cells through frameshift mutations

et al. 2020

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“…ATM acts as the central coordinator of the cellular response to DNA double strand breaks (DSB)[ 50 ]. Previous studies also suggest ATM participates in the response to replicative stress, in the mitotic spindle checkpoint and in cytoplasmic pathways, for example, the mobilization of calcium and potassium ions [ 51 – 55 ]. Additionally, ATR is a member of DDR that works during replicative stress by suppressing new origin firing, protecting and reactivating stalled forks, and preventing mitotic anomalies, including chromosome fragmentation [ 56 – 58 ].…”

Section: Discussionmentioning

confidence: 99%

Selective human inhibitors of ATR and ATM render Leishmania major promastigotes sensitive to oxidative damage

et al. 2018

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All cellular processes, including those involved in normal cell metabolism to those responsible for cell proliferation or death, are finely controlled by cell signaling pathways, whose core proteins constitute the family of phosphatidylinositol 3-kinase-related kinases (PIKKs). Ataxia Telangiectasia Mutated (ATM) and Ataxia Telangiectasia and Rad3 related (ATR) are two important PIKK proteins that act in response to DNA damage, phosphorylating a large number of proteins to exert control over genomic integrity. The genus Leishmania belongs to a group of early divergent eukaryotes in evolution and has a highly plastic genome, probably owing to the existence of signaling pathways designed to maintain genomic integrity. The objective of this study was to evaluate the use of specific human inhibitors of ATR and ATM in Leishmania major. Bioinformatic analyses revealed the existence of the putative PIKK genes ATR and ATM, in addition to mTOR and DNA-PKcs in Leishmania spp. Moreover, it was possible to suggest that the inhibitors VE-821 and KU-55933 have binding affinity for the catalytic sites of putative L. major ATR and ATM, respectively. Promastigotes of L. major exposed to these inhibitors show slight growth impairment and minor changes in cell cycle and morphology. It is noteworthy that treatment of promastigotes with inhibitors VE-821 and KU-55933 enhanced the oxidative damage caused by hydrogen peroxide. These inhibitors could significantly reduce the number of surviving L. major cells following H2O2 exposure whilst also decreasing their evaluated IC50 to H2O2 to less than half of that observed for non-treated cells. These results suggest that the use of specific inhibitors of ATR and ATM in Leishmania interferes in the signaling pathways of this parasite, which can impair its tolerance to DNA damage and affect its genome integrity. ATR and ATM could constitute novel targets for drug development and/or repositioning for treatment of leishmaniases.

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“…The level of hypoxia associated with radiation resistance, radiobiological hypoxia (<0.13% O 2 ), is characterised by a rapid induction of replication stress, which is defined as the slowing or stalling of replication forks. We have attributed hypoxia-induced replication stress to decreased nucleotide availability [2][3][4] . Previously, we demonstrated that hypoxia-induced replication stress leads to the induction of an ATR-and ATMdependent DNA damage response (DDR).…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-induced SETX links replication stress with the unfolded protein response

Ramachandran

et al. 2020

Preprint

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The levels of hypoxia associated with resistance to radiotherapy significantly impact cancer patient prognosis. These levels of hypoxia initiate a unique transcriptional response with the rapid activation of numerous transcription factors in a background of global repression of transcription. Here, weshow that the biological response to radiobiological hypoxia includes the induction of the DNA/RNA helicase SETX. In the absence of hypoxia-induced SETX, R-loop levels increase, DNA damage accumulates, and DNA replication rates decrease. SETX plays a key role in protecting cells from DNA damage induced during transcription in hypoxia. Importantly, we show that the mechanism of SETX induction is reliant on the PERK/ATF4 arm of the unfolded protein response. These data not only highlight the unique cellular response to radiobiological hypoxia, which includes both a replication stress dependent DNA damage response and an unfolded protein response but uncover a novel link between these two distinct pathways. Ramachandran et al.,

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Challenges to DNA replication in hypoxic conditions

Cited by 48 publications

References 79 publications

Hypoxia increases mutational load of breast cancer cells through frameshift mutations

Hypoxia increases mutational load of breast cancer cells through frameshift mutations

Selective human inhibitors of ATR and ATM render Leishmania major promastigotes sensitive to oxidative damage

Hypoxia-induced SETX links replication stress with the unfolded protein response

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