bims-ectoca 2024-12-15 papers

Issue of 2024–12–15
five papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Life Sci Alliance. 2025 Feb;pii: e202402870. [Epub ahead of print]8(2):

Depleting chemoresponsive mitochondrial fission mediator DRP1 does not mitigate sarcoma resistance.

Karolina Borankova, Matyas Solny, Maria Krchniakova, Jan Skoda.

Specific patterns of mitochondrial dynamics have been repeatedly reported to promote drug resistance in cancer. However, whether targeting mitochondrial fission- and fusion-related proteins could be leveraged to combat multidrug-resistant pediatric sarcomas is poorly understood. Here, we demonstrated that the expression and activation of the mitochondrial fission mediator DRP1 are affected by chemotherapy exposure in common pediatric sarcomas, namely, rhabdomyosarcoma and osteosarcoma. Unexpectedly, decreasing DRP1 activity through stable DRP1 knockdown neither attenuated sarcoma drug resistance nor affected growth rate or mitochondrial network morphology. The minimal impact on sarcoma cell physiology, along with the up-regulation of fission adaptor proteins (MFF and FIS1) detected in rhabdomyosarcoma cells, suggests an alternative DRP1-independent mitochondrial fission mechanism that may efficiently compensate for the lack of DRP1 activity. By exploring the upstream mitophagy and mitochondrial fission regulator, AMPKα1, we found that markedly reduced AMPKα1 levels are sufficient to maintain AMPK signaling capacity without affecting chemosensitivity. Collectively, our findings challenge the direct involvement of DRP1 in pediatric sarcoma drug resistance and highlight the complexity of yet-to-be-characterized noncanonical regulators of mitochondrial dynamics.

DOI: https://doi.org/10.26508/lsa.202402870

Brief Bioinform. 2024 Nov 22. pii: bbae638. [Epub ahead of print]26(1):

Understanding relationships between epigenetic marks and their application to robust assignment of chromatin states.

Leandro Murgas, Gianluca Pollastri, Erick Riquelme, Mauricio Sáez, Alberto J M Martin.

Structural changes of chromatin modulate access to DNA for the molecular machinery involved in the control of transcription. These changes are linked to variations in epigenetic marks that allow to classify chromatin in different functional states depending on the pattern of these histone marks. Importantly, alterations in chromatin states are known to be linked with various diseases, and their changes are known to explain processes such as cellular proliferation. For most of the available samples, there are not enough epigenomic data available to accurately determine chromatin states for the cells affected in each of them. This is mainly due to high costs of performing this type of experiments but also because of lack of a sufficient amount of sample or its degradation. In this work, we describe a cascade method based on a random forest algorithm to infer epigenetic marks, and by doing so, to identify relationships between different histone marks. Importantly, our approach also reduces the number of experimentally determined marks required to assign chromatin states. Moreover, in this work we have identified several relationships between patterns of different histone marks, which strengthens the evidence in favor of a redundant epigenetic code.

Keywords: Random Forest; chromatin states; epigenetic marks

DOI: https://doi.org/10.1093/bib/bbae638

Curr Opin Cell Biol. 2024 Dec 12. pii: S0955-0674(24)00127-3. [Epub ahead of print]92 102448

Topological epigenetics: The biophysics of DNA supercoiling and its relation to transcription and genome instability.

Nick Gilbert, Davide Marenduzzo.

Whilst DNA encodes our genetic blueprint as individual nucleobases, as well as epigenetic annotations in the form of biochemical marks, it also carries an extra layer of topological information -, the local over or underwinding of the double helix, known as DNA supercoiling. Supercoiling is a fundamental property of DNA that can be viewed as "topological epigenetics": it stores energy and structural information, and is tightly linked to fundamental processes; however, its quantification and study, by experiments and modelling alike, is challenging. We review experimental and simulation techniques to study supercoiling and its partition into twist and writhe, especially in the context of chromatin. We then discuss the dynamics of transcription-driven supercoiling in vitro and in vivo, and of supercoiling propagation along mammalian genomes. We finally provide evidence from the literature and potential mechanisms linking this ethereal topological mark to gene expression and chromosome instabilities in genetic diseases and cancer.

Keywords: Supercoiling; chromatin; chromosome instability; common fragile sites; transcription

DOI: https://doi.org/10.1016/j.ceb.2024.102448

Phys Med. 2024 Dec 11. pii: S1120-1797(24)01339-5. [Epub ahead of print]129 104871

Simulation of cell cycle effects on DNA strand break induction due to α-particles.

Laura Ballisat, Chiara De Sio, Lana Beck, Anna L Chambers, Mark S Dillingham, Susanna Guatelli, Dousatsu Sakata, Yuyao Shi, Jinyan Duan, Jaap Velthuis, Anatoly Rosenfeld.

PURPOSE: Understanding cell cycle variations in radiosensitivity is important for α-particle therapies. Differences are due to both repair response mechanisms and the quantity of initial radiation-induced DNA strand breaks. Genome compaction within the nucleus has been shown to impact the yield of strand breaks. Compaction changes during the cell cycle are therefore likely to contribute to radiosensitivity differences. Simulation allows the strand break yield to be calculated independently of repair mechanisms which would be challenging experimentally.
METHODS: Using Geant4 the impact of genome compaction changes on strand break induction due to α-particles was simulated. Genome compaction is considered to be described by three metrics: global base pair density, chromatin fibre packing fraction and chromosome condensation. Nuclei in the G1, S, G2 and M phases from two cancer cell lines and one normal cell line are simulated. Repair mechanisms are not considered to study only the impact of genome compaction changes.
RESULTS: The three compaction metrics have differing effects on the strand break yield. For all cell lines the strand break yield is greatest in G2 cells and least in G1 cells. More strand breaks are induced in the two cancer cell lines than in the normal cell line.
CONCLUSIONS: Compaction of the genome affects the initial yield of strand breaks. Some radiosensitivity differences between cell lines can be attributed to genome compaction changes between the phases of the cell cycle. This study provides a basis for further analysis of how repair deficiencies impact radiation-induced lethality in normal and malignant cells.

Keywords: Cell cycle; DNA damage; Geant4-DNA; Monte Carlo simulation

DOI: https://doi.org/10.1016/j.ejmp.2024.104871

Biol Pharm Bull. 2024 ;47(12): 1992-2002

Exploration of Novel Metabolic Features Reflecting Statin Sensitivity in Lung Cancer Cells.

Jiro Tashiro, Tomoko Warita, Akihiro Sugiura, Kana Mizoguchi, Takuro Ishikawa, Katsuhiko Warita.

Statins are cholesterol-lowering drugs often used for the treatment of dyslipidemia. Statins also exert anti-cancer effects by inhibiting hydroxymethylglutaryl-CoA reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis. We previously reported that the susceptibility to statin treatment differs among cancer cells and that functional E-cadherin expression on the plasma membrane could be a biomarker of statin sensitivity in cancer cells. However, the detailed qualitative and molecular differences between statin-sensitive and statin-resistant cancer cells remain unclear. Here, we explored novel parameters related to statin sensitivity by comparing gene expression profiles and metabolite contents between statin-sensitive and statin-resistant lung cancer cell lines. We found that the expression of most cholesterol synthesis genes was lower in the statin-sensitive cancer cell line, HOP-92, than in the statin-resistant cancer cell line, NCI-H322M. Moreover, HOP-92 cells originally exhibited lower levels of CoA and HMG-CoA. Additionally, atorvastatin decreased the mRNA expression of PANK2, a rate-limiting enzyme in CoA synthesis. Atorvastatin also reduced the mRNA levels of the cholesterol esterification enzyme SOAT1, which was consistent with a decrease in the ratio of cholesterol ester to total cholesterol in HOP-92 cells. Our data suggest that the cholesterol synthetic flow and CoA content may be limited in statin-sensitive cancer cells. We also suggest that CoA synthesis and cholesterol storage may fluctuate with atorvastatin treatment in statin-sensitive cancer cells.

Keywords: CoA; cancer; cholesterol; pantothenate kinase 2 (PANK2); statin sensitivity; sterol O-acyltransferase 1 (SOAT1)

DOI: https://doi.org/10.1248/bpb.b24-00346