scholarly journals Naked mole rat cells display more efficient DNA excision repair and higher resistance to toxic impacts than mouse cells

2020 ◽  
Vol 22 ◽  
pp. 01017
Author(s):  
Alexey Evdokimov ◽  
Irina Petruseva ◽  
Aleksei Popov ◽  
Olga Koval ◽  
Olga Lavrik
Keyword(s):  
Cell Death ◽  
Mus Musculus ◽  
Excision Repair ◽  
Genotoxic Stress ◽  
Cancer Resistance ◽  
Dna Excision Repair ◽  
Cell Defense ◽  
Regulated Cell Death ◽  
Mole Rat ◽  
Naked Mole Rat

Naked mole rat is the long-lived and tumor-resistant rodent. Naked mole rat possesses multiple adaptations that may contribute to longevity and cancer-resistance. Higher activity of DNA excision repair systems and their faster recovery after genotoxic impact as compare with Mus musculus directly demonstrated in our previous investigation contribute to longevity and cancer resistance of naked mole rat. In the present study the DNA-damage-induced apoptosis in naked mole rat fibroblasts was studied using conventional methods. The ability of naked mole rat cells to undergo regulated cell death in response to genotoxic stress is another group of cell defense mechanisms. Naked mole rat skin fibroblasts were demonstrated to be much more resistant towards proapoptotic reagents methyl methanesulfonate, 5-fluorouracil and etoposide as compared with fibroblasts of Mus musculus. Naked mole rat cells have demonstrated limited apoptotic response and seem to undergo also other-type regulated cell death under severe genotoxic stress.

scholarly journals Genome Stability Maintenance in Naked Mole-Rat

Acta Naturae ◽  
2017 ◽  
Vol 9 (4) ◽  
pp. 31-41 ◽  
Author(s):  
I. O. Petruseva ◽  
A. N. Evdokimov ◽  
O. I. Lavrik
Keyword(s):  
Molecular Basis ◽  
Genome Stability ◽  
High Stability ◽  
Replicative Senescence ◽  
Genotoxic Stress ◽  
Phenotypic Traits ◽  
Cancer Resistance ◽  
Effective Functioning ◽  
Mole Rat ◽  
Naked Mole Rat

The naked mole-rat (Heterocephalus glaber) is one of the most promising models used to study genome maintenance systems, including the effective repair of damage to DNA. The naked mole-rat is the longest lived rodent species, which is extraordinarily resistant to cancer and has a number of other unique phenotypic traits. For at least 80% of its lifespan, this animal shows no signs of aging or any increased likelihood of death and retains the ability to reproduce. The naked mole-rat draws the heightened attention of researchers who study the molecular basis of lengthy lifespan and cancer resistance. Despite the fact that the naked mole-rat lives under genotoxic stress conditions (oxidative, etc.), the main characteristics of its genome and proteome are a high stability and effective functioning. Replicative senescence in the somatic cells of naked mole-rats is missing, while an additional p53/pRb-dependent mechanism of early contact inhibition has been revealed in its fibroblasts, which controls cell proliferation and its mechanism of arf-dependent aging. The unique traits of phenotypic and molecular adaptations found in the naked mole-rat speak to a high stability and effective functioning of the molecular machinery that counteract damage accumulation in its genome. This review analyzes existing results in the study of the molecular basis of longevity and high cancer resistance in naked mole-rats.

scholarly journals Uncovering molecular mechanisms of regulated cell death in the naked mole rat

Aging ◽  
2021 ◽  
Author(s):  
Alexei Evdokimov ◽  
Alexei Popov ◽  
Elena Ryabchikova ◽  
Olga Koval ◽  
Svetlana Romanenko ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Regulated Cell Death ◽  
Mole Rat ◽  
Naked Mole Rat

The use of non-traditional models in the study of cancer resistance—the case of the naked mole rat

Oncogene ◽  
2020 ◽  
Vol 39 (28) ◽  
pp. 5083-5097 ◽  
Author(s):  
Alyssa Shepard ◽  
Joseph L. Kissil
Keyword(s):  
Cancer Resistance ◽  
Mole Rat ◽  
Naked Mole Rat

scholarly journals Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

2015 ◽  
Vol 11 (5) ◽  
pp. 20150185 ◽  
Author(s):  
Christopher G. Faulkes ◽  
Kalina T. J. Davies ◽  
Stephen J. Rossiter ◽  
Nigel C. Bennett
Keyword(s):  
Purifying Selection ◽  
High Molecular Mass ◽  
Hyaluronan Synthase ◽  
Cancer Resistance ◽  
Closely Related Species ◽  
Heterocephalus Glaber ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Subterranean Mammals ◽  
Hyaluronan Synthase 2

The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan—a key constituent of the extracellular matrix—that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African mole-rat clade.

scholarly journals Dampened PI3K/AKT signaling contributes to cancer resistance of the naked mole rat

2020 ◽  
Author(s):  
Jing Zhao ◽  
Xiao Tian ◽  
Yabing Zhu ◽  
Zhihui Zhang ◽  
Elena Rydkina ◽  
...  
Keyword(s):  
Cancer Susceptibility ◽  
Mammalian Species ◽  
Pi3k Pathway ◽  
Human Cells ◽  
Cancer Resistance ◽  
Tumor Resistance ◽  
Resistant Species ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Transcriptional Changes

AbstractMammalian species have a dramatically different susceptibility to cancer. However, how cancer-resistant species resist oncogenic transformation is not fully understood. Here, we performed a comprehensive analysis of oncogene-induced transcriptional changes in the fibroblasts of a cancer-prone species, the mouse, and three cancer-resistant species, the human, the blind mole rat, and the naked mole rat. We report that multiple cellular processes are more refractory to oncogene-induced transcriptional changes in blind mole-rat, naked mole-rat, or human cells compared to mouse cells, such as cell division, cell adhesion, extracellular matrix organization, and metabolism. Strikingly, naked mole rat cells are more resistant to Ras-induced transcriptional changes compared to the other three species. As a mechanism, we found that critical genes in the PI3K pathway including Akt1 and Pik3ca are downregulated in naked mole rat cells. Activating the PI3K/AKT pathway in the naked mole rat cells renders them susceptible to tumorigenic transformation. This study provides multiple new insights into anti-cancer mechanisms in cancer-resistant species of mammals.Significance statementAnimal species differ greatly in their cancer susceptibility. Cancer rates in the mouse range from 50-90%, while two other rodent species, the naked mole rat and the blind mole rat have only a few cancer cases ever reported. Here we examined the mechanisms responsible these differences by comparing changes in transcription patters in response to oncoproteins in the mouse, naked mole rat, blind mole rat and human cells. The most striking finding was that the naked mole rat cells were resistant to transcriptional changes induced by oncogenic Ras. We found that pathways downstream of Ras were naturally attenuated in the naked mole rat. This finding identifies a novel mechanism that evolved to provide tumor resistance to the naked mole rat.

scholarly journals Imiquimod does not elicit inflammatory responses in the skin of the naked mole rat (Heterocephalus glaber)

2020 ◽  
Author(s):  
Mosiany Letura Kisipan ◽  
Rodi Omondi Ojoo ◽  
Titus I. Kanui ◽  
Klas S.P. Abelson
Keyword(s):  
Granular Layer ◽  
Inflammatory Responses ◽  
Cancer Resistance ◽  
Skin Reactions ◽  
Heterocephalus Glaber ◽  
Skin Changes ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Inflammatory Skin ◽  
Skin Conditions

Abstract Objective: Naked mole rat (Heterocephalus glaber) has recently attracted interest in biomedical research due to its exceptional longevity, cancer resistance and tolerance to potentially harmful conditions or stimuli. Given its unique attributes, this study was designed to characterize inflammatory skin reactions of this animal to topical application of imiquimod, a toll-like receptor 7 and 8 agonist that triggers psoriasis-like skin reaction. Results: Imiquimod did not cause the expected psoriasis-like skin changes. There was no epidermal thickening and a straight epidermo-dermal boundary was maintained. There was no parakeratosis and the granular layer of epidermis was well formed. In the dermis, there was no leukocyte infiltration. This points to an exceptional nature of inflammatory/immune responses of this animal, but the mechanism could not be explained by our results. Naked mole rat could be a valuable negative model for studying psoriasis and other inflammatory skin conditions but as a prerequisite, there is need for further investigations to establish the mechanisms behind its lack of response to imiquimod.

scholarly journals High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat

Nature ◽  
2013 ◽  
Vol 499 (7458) ◽  
pp. 346-349 ◽  
Author(s):  
Xiao Tian ◽  
Jorge Azpurua ◽  
Christopher Hine ◽  
Amita Vaidya ◽  
Max Myakishev-Rempel ◽  
...  
Keyword(s):  
Molecular Mass ◽  
High Molecular Mass ◽  
Cancer Resistance ◽  
Mole Rat ◽  
Naked Mole Rat

scholarly journals DNA Excision Repair and DNA Damage-Induced Apoptosis Are Linked to Poly(ADP-Ribosyl)ation but Have Different Requirements for p53

2000 ◽  
Vol 20 (18) ◽  
pp. 6695-6703 ◽  
Author(s):  
Ralph Beneke ◽  
Christoph Geisen ◽  
Branko Zevnik ◽  
Thomas Bauch ◽  
Wolfgang-Ulrich Müller ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Zinc Finger Protein ◽  
Excision Repair ◽  
Dna Breaks ◽  
In Vivo Models ◽  
P53 Expression ◽  
Dna Excision Repair ◽  
Parp Activity

ABSTRACT Poly(ADP-ribose) polymerase (PARP) is a DNA binding zinc finger protein that catalyzes the transfer of ADP-ribose residues from NAD+ to itself and different chromatin constituents, forming branched ADP-ribose polymers. The enzymatic activity of PARP is induced upon DNA damage and the PARP protein is cleaved during apoptosis, which suggested a role of PARP in DNA repair and DNA damage-induced cell death. We have generated transgenic mice that lack PARP activity in thymocytes owing to the targeted expression of a dominant negative form of PARP. In the presence of single-strand DNA breaks, the absence of PARP activity correlated with a strongly increased rate of apoptosis compared to cells with intact PARP activity. We found that blockage of PARP activity leads to a drastic increase of p53 expression and activity after DNA damage and correlates with an accelerated onset of Bax expression. DNA repair is almost completely blocked in PARP-deficient thymocytes regardless of p53 status. We found the same increased susceptibility to apoptosis in PARP null mice, a similar inhibition of DNA repair kinetics, and the same upregulation of p53 in response to DNA damage. Thus, based on two different experimental in vivo models, we identify a direct, p53-independent, functional connection between poly(ADP-ribosyl)ation and the DNA excision repair machinery. Furthermore, we propose a p53-dependent link between PARP activity and DNA damage-induced cell death.

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