Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Molinaro, Caroline; Martoriati, Alain; Cailliau, Katia

doi:10.3390/cancers13153819

Cited by 25 publications

(15 citation statements)

References 365 publications

(403 reference statements)

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“…Proteins that operate in DNA damage responses are thoroughly regulated with different strategies, such as post-translational modifications or binding partner proteins for activity modulation [ 117 ]. PrimPol is not an exception to this rule.…”

Section: Structure and Regulation Of Human Primpolmentioning

confidence: 99%

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

et al. 2022

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DNA replication can encounter blocking obstacles, leading to replication stress and genome instability. There are several mechanisms for evading this blockade. One mechanism consists of repriming ahead of the obstacles, creating a new starting point; in humans, PrimPol is responsible for carrying out this task. PrimPol is a primase that operates in both the nucleus and mitochondria. In contrast with convectional primases, PrimPol is a DNA primase able to initiate DNA synthesis de novo using deoxynucleotides, discriminating against ribonucleotides. In vitro, PrimPol can act as a translesion synthesis (TLS) DNA primase, elongating primers that PrimPol itself sythesizes, or as TLS DNA polymerase, elongating pre-existing primers across lesions. However, the lack of evidence for PrimPol polymerase activity in vivo suggests that PrimPol only uses its TLS abilities to facilitate priming across lesions in cells, thus acting as a TLS DNA primase. Here, we provide a comprehensive review of human PrimPol covering its biochemical properties and structure, in vivo function and regulation, and the processes that take place to fill the gap-containing lesion that PrimPol leaves behind. Finally, we explore the available data on human PrimPol expression in different tissues in physiological conditions and its role in cancer.

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Section: Structure and Regulation Of Human Primpolmentioning

confidence: 99%

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

et al. 2022

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“…We then determined whether WN197 and WN170 could induce autophagy. In the three adenocarcinoma cell lines, several autophagy markers ( 63 ) were detected. p62/sequestosome-1 was degraded, Beclin-1 was synthesized and LC3-I association with phosphatidyl-ethanolamine that forms LC3-II was increased as shown by accumulation of LC3-II after 24h of treatment with 0.5 µM of WN197 and WN170 ( Figure 7D ).…”

Section: Resultsmentioning

confidence: 99%

A Novel Copper(II) Indenoisoquinoline Complex Inhibits Topoisomerase I, Induces G2 Phase Arrest, and Autophagy in Three Adenocarcinomas

Molinaro

Wambang

Bousquet³

et al. 2022

Front. Oncol.

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Topoisomerases, targets of inhibitors used in chemotherapy, induce DNA breaks accumulation leading to cancer cell death. A newly synthesized copper(II) indenoisoquinoline complex WN197 exhibits a cytotoxic effect below 0.5 µM, on MDA-MB-231, HeLa, and HT-29 cells. At low doses, WN197 inhibits topoisomerase I. At higher doses, it inhibits topoisomerase IIα and IIβ, and displays DNA intercalation properties. DNA damage is detected by the presence of γH2AX. The activation of the DNA Damage Response (DDR) occurs through the phosphorylation of ATM/ATR, Chk1/2 kinases, and the increase of p21, a p53 target. WN197 induces a G2 phase arrest characterized by the unphosphorylated form of histone H3, the accumulation of phosphorylated Cdk1, and an association of Cdc25C with 14.3.3. Cancer cells die by autophagy with Beclin-1 accumulation, LC3-II formation, p62 degradation, and RAPTOR phosphorylation in the mTOR complex. Finally, WN197 by inhibiting topoisomerase I at low concentration with high efficiency is a promising agent for the development of future DNA damaging chemotherapies.

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“…In addition to transient effects such as heart rate changes or immune cell trafficking, the increased production of sympathetic and other adrenal hormones in response to stress causes long-lasting consequences such as permanent DNA damage, which results in increased cell transformation and/or tumorigenicity. Stress hormones can induce DNA damage sensors such as Chk1, Chk2 and E3 ubiquitin-protein ligase Mdm2, and the resulting DNA damage can trigger cellular responses, including cell cycle checkpoint activity, apoptosis and DNA repair pathways (62)(63)(64). However, few studies have explored the mechanism by which stress hormones impact cancer progression via the induction of DNA damage.…”

Section: Discussionmentioning

confidence: 99%

Wip1 contributes to the adaptation of HepG2 human liver cancer cells to stress hormone‑induced DNA damage

Qian

Chen

et al. 2022

Oncol Lett

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Numerous studies have shown that the release of stress hormones resulting from repeated exposure to chronic psychological stress increases DNA damage and promotes tumorigenesis. However, the mechanisms that enable cancerous cells adapt to stress hormone-induced DNA damage and survive remain unclear. The present study aimed to investigate the impact of stress hormones on the survival of liver cancer cells and the underlying mechanism. HepG2 human liver cancer cells were treated with dexamethasone (DEX), epinephrine (EPI) and norepinephrine (NE) and subjected to the testing of DNA damage, cell survival and cell apoptosis by alkaline comet assay, CCK-8 viability assay and flow cytometry, respectively. The protein expression levels of DNA damage response factors were determined by western blotting analysis. The results revealed that treatment of HepG2 cells with DEX, EPI and NE induced DNA damage without affecting cell survival or inducing apoptosis. The protein levels of wild-type p53-induced phosphatase 1 (Wip1), a type 2C family serine/threonine phosphatase, were increased, and the dephosphorylation of DNA damage response factors, including phosphorylated (p-)ataxia-telangiectasia mutated and p-checkpoint kinase 2, occurred following treatment with DEX, EPI and NE. In addition, a cycloheximide chase assay was performed to explore the protein stability under treatment with stress hormones. Compared with vehicle-treated cells, Wip1 exhibited increased protein stability in stress hormone-treated HepG2 cells. Eventually, the depletion of Wip1 using small interfering RNA verified the role of Wip1 in the modulation of stress hormone-induced DNA damage. These findings suggest that cancerous cells likely adapt to stress hormone-induced DNA damage via Wip1 upregulation. The present study provides an insight into the underlying mechanism that links chronic psychological stress with tumor growth and progression.

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Proteins from the DNA Damage Response: Regulation, Dysfunction, and Anticancer Strategies

Cited by 25 publications

References 365 publications

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

PrimPol: A Breakthrough among DNA Replication Enzymes and a Potential New Target for Cancer Therapy

A Novel Copper(II) Indenoisoquinoline Complex Inhibits Topoisomerase I, Induces G2 Phase Arrest, and Autophagy in Three Adenocarcinomas

Wip1 contributes to the adaptation of HepG2 human liver cancer cells to stress hormone‑induced DNA damage

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