Mechanisms of DNA damage, repair, and mutagenesis

Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states. However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. Environ. Mol. Mutagen. 58:235–263, 2017 © 2017 Wiley Periodicals, Inc.National Institute of Environmental Health Sciences (Grant ES-015818

REV1 Inhibition Enhances Radioresistance and Autophagy

SIMPLE SUMMARY: Cancer resistance to therapy continues to be the biggest challenge in treating patients. Targeting the mutagenic translesion synthesis (TLS) polymerase REV1 was previously shown to sensitize cancer cells to chemotherapy. In this study, we tested the ability of REV1 inhibitors to radiation therapy and observed a lack of radiosensitization. In addition, we observed REV1 inhibition to trigger an autophagy stress response. Because reduction of REV1 triggered autophagy and failed to radiosensitize cells, we hypothesize REV1 expression dynamics might link cancer cell response to radiation treatment through the potential induction of autophagy. ABSTRACT: Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations suggest REV1’s important role in determining cancer cell response to chemotherapy. Whether REV1 inhibition would similarly sensitize cancer cells to radiation treatment is unknown. This study reports a lack of radiosensitization in response to REV1 inhibition by small molecule inhibitors in ionizing radiation-exposed cancer cells. Instead, REV1 inhibition unexpectedly triggers autophagy, which is a known biomarker of radioresistance. We report a possible role of the REV1 TLS protein in determining cancer treatment outcomes depending upon the type of DNA damage inflicted. Furthermore, we discover that REV1 inhibition directly triggers autophagy, an uncharacterized REV1 phenotype, with a significant bearing on cancer treatment regimens

REV1 inhibition elicits differential response to cancer therapy

Translesion synthesis (TLS) is a DNA damage tolerance mechanism that acts to bypass lesions at stalled replication forks. Recently, TLS has been implicated in cancer resistance to chemotherapy as it allows replication of DNA over genotoxic insults to promote cancer cell proliferation. Targeting the central scaffolding protein in this process, REV1, has emerged as a potential method for sensitizing cancer cells to chemotherapy. Most notably, REV1 inhibition sensitizes cancer cells to cisplatin treatment. We further investigated whether REV1 inhibition could sensitize cancer cells to ionizing radiation (IR). Here, we report that REV1 inhibition confers radioresistance and triggers the induction of autophagy which is modulated by different DNA-damaging agents. This radioresistant phenotype is observed in vitro and in vivo. These findings present REV1 and TLS as modulators of response to various types of DNA damaging therapies and warrant further study to determine the therapeutic potential of REV1 inhibition

Inhibition of mutagenic translesion synthesis: A possible strategy for improving chemotherapy?

With the recent technological developments a vast amount of high-throughput data has been profiled to understand the mechanism of complex diseases. The current bioinformatics challenge is to interpret the data and underlying biology, where efficient algorithms for analyzing heterogeneous high-throughput data using biological networks are becoming increasingly valuable. In this paper, we propose a software package based on the Prize-collecting Steiner Forest graph optimization approach. The PCSF package performs fast and user-friendly network analysis of high-throughput data by mapping the data onto a biological networks such as protein-protein interaction, gene-gene interaction or any other correlation or coexpression based networks. Using the interaction networks as a template, it determines high-confidence subnetworks relevant to the data, which potentially leads to predictions of functional units. It also interactively visualizes the resulting subnetwork with functional enrichment analysis.National Institute of Environmental Health Sciences (Grant ES015818)National Institute of Environmental Health Sciences (Grant P30 ES002109)Virginia and D.K. Ludwig Fund for Cancer Researc

The Cultural Context of Plagiarism and Research Misconduct in the Asian Region

Plagiarism is one of the most frequent forms of research misconduct in South and East Asian countries. This narrative review examines the factors contributing to research misconduct, emphasizing plagiarism, particularly in South, East and Southeast Asian countries. We conducted a PubMed and Scopus search using the terms plagiarism, Asia, South Asia, East Asia, Southeast Asia, research misconduct and retractions in January of 2022. Articles with missing abstracts, incomplete information about plagiarism, publication dates before 2010, and those unrelated to South, East, and Southeast Asian countries were excluded. The retraction watch database was searched for articles retracted between 9th January 2020 to 9th January 2022. A total of 159 articles were identified, of which 21 were included in the study using the database search criteria mentioned above. The review of articles identified a lack of training in scientific writing and research ethics, publication pressure, permissive attitudes, and inadequate regulatory measures as the primary reasons behind research misconduct in scientific publications. Plagiarism remains a common cause of unethical publications and retractions in regions of Asia (namely South, East and Southeast). Researchers lack training in scientific writing, and substantial gaps exist in understanding various forms of plagiarism, which heavily contribute to the problem. There is an urgent need to foster high research ethics standards and adhere to journal policies. Providing appropriate training in scientific writing among researchers may help improve the knowledge of different types of plagiarism and promote the use of antiplagiarism software, leading to a substantial reduction in the problem

The social media Infodemic of health-related misinformation and technical solutions

This paper discusses the role of social media algorithms in the spread of misinformation during the COVID-19 pandemic. It aims to propose solutions to combat misinformation and promote accurate, evidence-based public health information.</p

Summary of the characteristics, expression, the availability of mouse model, and association to cancers of B- and Y-family translesion synthesis polymerases.

<p>Summary of the characteristics, expression, the availability of mouse model, and association to cancers of B- and Y-family translesion synthesis polymerases.</p

DNA damage bypass process.

<p>(A) Mechanism of the 2-step DNA damage bypass process. To bypass DNA damage, REV1 inserts deoxycytidine triphosphates across the damage or orchestrates the recruitment of the other polymerases, POL ι, POL κ, POL η, to replicate across the damage. Thereafter, POL ζ complex can help extend beyond the damage to enable re-initiation of undamaged DNA replication. If an incorrect nucleotide gets incorporated across the damage, this misincorporated nucleotide will lead to a mutation in the next round of replication. (B) A schematic representing the protein domains of the Y-family translesion synthesis (TLS) polymerases, REV1, POL ι, POL κ, POL η.</p