scholarly journals A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator

2018 ◽  
Vol 9 (4) ◽  
pp. 841-849 ◽  
Author(s):  
Martin R. Gill ◽  
Paul J. Jarman ◽  
Swagata Halder ◽  
Michael G. Walker ◽  
Hiwa K. Saeed ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cancer Cells ◽  
Oesophageal Cancer ◽  
Replication Fork ◽  
Ionising Radiation ◽  
Spindle Attachment

[Ru(phen)2(tpphz)]2+ simultaneously inhibits DNA replication, blocks mitosis and enhances DNA-damaging ionising radiation in oesophageal cancer cells.

scholarly journals A ruthenium polypyridyl intercalator stalls DNA replication forks, radiosensitizes human cancer cells and is enhanced by Chk1 inhibition

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Martin R. Gill ◽  
Siti Norain Harun ◽  
Swagata Halder ◽  
Ramon A. Boghozian ◽  
Kristijan Ramadan ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Dna Damage ◽  
Dna Replication ◽  
Cancer Cells ◽  
Replication Fork ◽  
Human Cancer ◽  
Cell Signalling ◽  
Ionising Radiation ◽  
Replication Forks ◽  
Replication Fork Progression

Abstract Ruthenium(II) polypyridyl complexes can intercalate DNA with high affinity and prevent cell proliferation; however, the direct impact of ruthenium-based intercalation on cellular DNA replication remains unknown. Here we show the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyridophenazine, PIP = 2-(phenyl)imidazo[4,5-f][1,10]phenanthroline) immediately stalls replication fork progression in HeLa human cervical cancer cells. In response to this replication blockade, the DNA damage response (DDR) cell signalling network is activated, with checkpoint kinase 1 (Chk1) activation indicating prolonged replication-associated DNA damage, and cell proliferation is inhibited by G1-S cell-cycle arrest. Co-incubation with a Chk1 inhibitor achieves synergistic apoptosis in cancer cells, with a significant increase in phospho(Ser139) histone H2AX (γ-H2AX) levels and foci indicating increased conversion of stalled replication forks to double-strand breaks (DSBs). Normal human epithelial cells remain unaffected by this concurrent treatment. Furthermore, pre-treatment of HeLa cells with [Ru(dppz)2(PIP)]2+ before external beam ionising radiation results in a supra-additive decrease in cell survival accompanied by increased γ-H2AX expression, indicating the compound functions as a radiosensitizer. Together, these results indicate ruthenium-based intercalation can block replication fork progression and demonstrate how these DNA-binding agents may be combined with DDR inhibitors or ionising radiation to achieve more efficient cancer cell killing.

scholarly journals MIF is a 3’ flap nuclease that facilitates DNA replication and promotes tumor growth

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yijie Wang ◽  
Yan Chen ◽  
Chenliang Wang ◽  
Mingming Yang ◽  
Yanan Wang ◽  
...  
Keyword(s):  
Dna Replication ◽  
Tumor Growth ◽  
Dna Synthesis ◽  
Cancer Cells ◽  
Macrophage Migration Inhibitory Factor ◽  
Replication Fork ◽  
Replication Stress ◽  
Nuclease Activity ◽  
Cell Growth Inhibition ◽  
Poor Overall Survival

AbstractHow cancer cells cope with high levels of replication stress during rapid proliferation is currently unclear. Here, we show that macrophage migration inhibitory factor (MIF) is a 3’ flap nuclease that translocates to the nucleus in S phase. Poly(ADP-ribose) polymerase 1 co-localizes with MIF to the DNA replication fork, where MIF nuclease activity is required to resolve replication stress and facilitates tumor growth. MIF loss in cancer cells leads to mutation frequency increases, cell cycle delays and DNA synthesis and cell growth inhibition, which can be rescued by restoring MIF, but not nuclease-deficient MIF mutant. MIF is significantly upregulated in breast tumors and correlates with poor overall survival in patients. We propose that MIF is a unique 3’ nuclease, excises flaps at the immediate 3’ end during DNA synthesis and favors cancer cells evading replication stress-induced threat for their growth.

scholarly journals cGAS suppresses genomic instability as a decelerator of replication forks

2020 ◽  
Vol 6 (42) ◽  
pp. eabb8941 ◽  
Author(s):  
Hao Chen ◽  
Hao Chen ◽  
Jiamin Zhang ◽  
Yumin Wang ◽  
Antoine Simoneau ◽  
...  
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Dna Replication ◽  
Cancer Cells ◽  
Genomic Instability ◽  
Cyclic Gmp ◽  
Replication Fork ◽  
Innate Immune ◽  
Dependent Manner ◽  
Replication Forks

The cyclic GMP-AMP synthase (cGAS), a sensor of cytosolic DNA, is critical for the innate immune response. Here, we show that loss of cGAS in untransformed and cancer cells results in uncontrolled DNA replication, hyperproliferation, and genomic instability. While the majority of cGAS is cytoplasmic, a fraction of cGAS associates with chromatin. cGAS interacts with replication fork proteins in a DNA binding–dependent manner, suggesting that cGAS encounters replication forks in DNA. Independent of cGAMP and STING, cGAS slows replication forks by binding to DNA in the nucleus. In the absence of cGAS, replication forks are accelerated, but fork stability is compromised. Consequently, cGAS-deficient cells are exposed to replication stress and become increasingly sensitive to radiation and chemotherapy. Thus, by acting as a decelerator of DNA replication forks, cGAS controls replication dynamics and suppresses replication-associated DNA damage, suggesting that cGAS is an attractive target for exploiting the genomic instability of cancer cells.

scholarly journals DOCK7 protects against replication stress by promoting RPA stability on chromatin

2021 ◽  
Vol 49 (6) ◽  
pp. 3322-3337
Author(s):  
Ming Gao ◽  
Guijie Guo ◽  
Jinzhou Huang ◽  
Xiaonan Hou ◽  
Hyoungjun Ham ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Replication ◽  
Stress Response ◽  
Cancer Cells ◽  
Replication Fork ◽  
Therapeutic Targets ◽  
Critical Factor ◽  
Replication Stress ◽  
Exchange Factor

Abstract RPA is a critical factor for DNA replication and replication stress response. Surprisingly, we found that chromatin RPA stability is tightly regulated. We report that the GDP/GTP exchange factor DOCK7 acts as a critical replication stress regulator to promote RPA stability on chromatin. DOCK7 is phosphorylated by ATR and then recruited by MDC1 to the chromatin and replication fork during replication stress. DOCK7-mediated Rac1/Cdc42 activation leads to the activation of PAK1, which subsequently phosphorylates RPA1 at S135 and T180 to stabilize chromatin-loaded RPA1 and ensure proper replication stress response. Moreover, DOCK7 is overexpressed in ovarian cancer and depleting DOCK7 sensitizes cancer cells to camptothecin. Taken together, our results highlight a novel role for DOCK7 in regulation of the replication stress response and highlight potential therapeutic targets to overcome chemoresistance in cancer.

scholarly journals Mechanistic Model of Replication Fork Progression in Yeast

2021 ◽  
Author(s):  
Ghanendra Singh
Keyword(s):  
Dna Replication ◽  
Cancer Cells ◽  
Replication Fork ◽  
Essential Role ◽  
Molecular Mechanisms ◽  
Molecular Level ◽  
Mechanistic Model ◽  
Normal Cells ◽  
Replication Fork Progression ◽  
Mammalian System

Replication fork progression complex plays an essential role during DNA replication. It travels along with the DNA with a particular speed called replication fork speed. Faithful duplication of the genome requires strict control over replication fork speed. Both acceleration and pausing mechanisms of the replication fork complex are regulated at the molecular level. Based on the experimental evidence, DNA replicates faster in normal cells than cancer cells, whereas cancer cells duplicate themselves more quickly than normal cells. Then in principle, accelerating the replication fork complex in cancer cells beyond a specific threshold speed limit can cause DNA damage and plausibly kill them. A modular mathematical model is proposed to explain the dynamics of replication fork control during DNA replication using the underlying molecular mechanisms in yeast which can extend to the mammalian system in the future.

scholarly journals MTA2 sensitizes gastric cancer cells to PARP inhibition by induction of DNA replication stress

2021 ◽  
Vol 14 (10) ◽  
pp. 101167
Author(s):  
Jinwen Shi ◽  
Xiaofeng Zhang ◽  
Jin'e Li ◽  
Wenwen Huang ◽  
Yini Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Replication ◽  
Cancer Cells ◽  
Replication Stress ◽  
Parp Inhibition ◽  
Gastric Cancer Cells ◽  
Dna Replication Stress

scholarly journals The yeast S phase checkpoint enables replicating chromosomes to bi-orient and restrain spindle extension during S phase distress

2005 ◽  
Vol 168 (7) ◽  
pp. 999-1012 ◽  
Author(s):  
Jeff Bachant ◽  
Shannon R. Jessen ◽  
Sarah E. Kavanaugh ◽  
Candida S. Fielding
Keyword(s):  
Dna Replication ◽  
Chromosome Segregation ◽  
Replication Fork ◽  
S Phase ◽  
Origin Of Replication ◽  
Independent Manner ◽  
Checkpoint Signaling ◽  
Hydroxyurea Treatment ◽  
Chromatid Cohesion ◽  
S Phase Checkpoint

The budding yeast S phase checkpoint responds to hydroxyurea-induced nucleotide depletion by preventing replication fork collapse and the segregation of unreplicated chromosomes. Although the block to chromosome segregation has been thought to occur by inhibiting anaphase, we show checkpoint-defective rad53 mutants undergo cycles of spindle extension and collapse after hydroxyurea treatment that are distinct from anaphase cells. Furthermore, chromatid cohesion, whose dissolution triggers anaphase, is dispensable for S phase checkpoint arrest. Kinetochore–spindle attachments are required to prevent spindle extension during replication blocks, and chromosomes with two centromeres or an origin of replication juxtaposed to a centromere rescue the rad53 checkpoint defect. These observations suggest that checkpoint signaling is required to generate an inward force involved in maintaining preanaphase spindle integrity during DNA replication distress. We propose that by promoting replication fork integrity under these conditions Rad53 ensures centromere duplication. Replicating chromosomes can then bi-orient in a cohesin-independent manner to restrain untimely spindle extension.

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