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  • SCH727965 Other factors also contribute to

    2020-10-05

    Other factors also contribute to replication fork progression in DNA damage conditions. For instance, the cullin Rtt101 has a role in fork movement through alkylated DNA, probably associated to a damage tolerance mechanism [52], and TORC signaling is also important for fork progression in response to genotoxic stress [53]. Some other mutants show defects in S phase progression in the presence of DNA damage [47] and it would be interesting to investigate whether the corresponding proteins have a role in promoting fork movement under those conditions. We still need to fully understand how all the pathways that cooperate to allow fork progression through damaged DNA are coordinated among themselves, with the replication machinery and with the components of the S phase checkpoint. A deeper understanding of SCH727965 all the aspects involved in the cellular response to DNA damage during replication might contribute to a better knowledge of the biology of tumor SCH727965 and to the future development of drugs for use in chemotherapy.
    Conflict of interest
    Acknowledgments
    Introduction Under current human health risk assessment practices, DNA-reactive agents are generally considered by regulatory agencies to have no thresholds for biological outcomes such as mutation and cancer [1]. The debate surrounding the linearity of low-dose effects related to genotoxicity and cancer has been on-going for decades. New understanding in biological mechanism and mode-of-action (MOA), along with new high-content and high-throughput approaches, and increasingly sensitive analytical methods, bring new evidence into this debate. New in vivo and in vitro data have demonstrated the existence of non-linear/bilinear dose–responses for genotoxic effects (i.e., a dose–response curve with a slope not significantly different from zero gradient below the estimated threshold or Break Point Dose (BPD)), where there is no significant difference in mutant frequency between the spontaneous background of control and the low-dose exposure region of DNA-reactive agents [2], [3], [4], [5], [6]. In recent years, new statistical approaches have also been developed and applied to analyze low-dose results to establish whether the dose–response is linear or non-linear/bilinear, derive a point of departure (PoD), and determine what impact the spontaneous background genotoxicity should have on risk assessment. These compelling, empirical dose–response data do not address the biological underpinnings of mutation at low-dose exposures per se and require focused investigations of the MOA behind these non-linear/bilinear dose–responses. For an expressed mutation, several key events must occur from the initial DNA adduct formation, including insufficient adduct repair, DNA replication and cell division. Moreover, endogenous DNA adducts are now recognized to be ubiquitously present at quantifiable levels in all living tissues. This new perception of the background exposome is shifting perspective on what is normal vs. adaptive vs. adverse [7], [8]. This review discusses the current understanding of biological, mechanistic processes that explain these PoDs, specifically DNA repair and DNA damage response, and complex interactions between these pathways. The detailed discussion presented here was initiated during a Society of Toxicology 2013 workshop entitled the Biology of the Low-Dose Response for DNA-Reactive Chemicals. A clear focus on molecular and biological approaches to defining and understanding consequences of DNA damage at the cellular level fits well with the 2007 NRC report, Toxicity Testing in the 21st Century: A Vision and A Strategy that envisions a future in which all routine testing will use cell-based in vitro assays of toxicity pathways [9], [10].
    New methods to investigate responses at low-dose exposures
    Alkylating agents
    DNA repair and break point doses
    Interactions between DNA repair and DDR pathways
    Profiling of biological pathways and genotoxic dose–response relationships