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  • Exposure to cisplatin with ATR inhibitor resulted in an incr

    2024-06-14

    Exposure to cisplatin with ATR inhibitor resulted in an increase in cisplatin-DNA adducts, especially in cells with ATM deficiency. This finding indicates that suppressing ATR-Chk1 signaling with VE-822 enhances cisplatin activity by enabling the drug to form DNA adducts. Therefore, VE-822 may increase cisplatin-DNA accumulation by hindering DNA damage repair induced by cisplatin-DNA. On the other hand, in the previous study, the cells treated with VE-822 along with cisplatin had decreased expression of p-glycoprotein. It inferred that VE-822 inhibited the expression of p-glycoprotein to prevent cisplatin efflux, then increasing its concentration [33].
    Conflicts of interest
    Author contribution
    Acknowledgements This work was supported by Beijing Municipal Administration of Hospitals Incubating Program (PX2018044); National Natural Science Foundation for Young Scholars (Grant 81301748); National High Technology Research and Development Program of China (2015AA020403); and Beijing Municipal Administration of hospitals Clinical Medicine Development of special funding support (ZYLX201509).
    Introduction The PF-562271 excision repair (BER) pathway repairs small chemical DNA base lesions such as those induced by the monofunctional alkylating agent methyl methanesulfonate (MMS). This is a step-by-step process involving excision of the damaged base followed by cleavage of the sugar phosphate backbone, thus generating a DNA single-strand break (SSB) which is subsequently resealed by a ligase [1], [2], [3], [4]. Alternative BER pathways exist which involve replacement of one (short patch BER) or more nucleotides (long patch BER) at the lesion site. BER-deficient cells are genetically unstable and sensitive to cell killing by a variety of genotoxins including MMS [5], [6], [7]. Considerable evidence suggests that this results from unrepaired lesions encountered by a replication fork, provoking either fork stalling or fork collapse after the conversion of a SSB to a double-strand break (DSB) [8], [9], [10], [11]. These DNA structures are also thought to serve as substrates for homologous recombination repair (HRR) and could be the mechanistic basis for the increased levels of damage-induced sister-chromatid exchange rates found in BER-deficient cells [12]. X-ray repair cross-complementing 1 (XRCC1) is a scaffold protein, which is required for efficient BER and SSB repair in mammalian cells. XRCC1-deficiency in mice causes embryonic lethality and mutant mouse or CHO cells without functional XRCC1 protein and human cell cultures where XRCC1 has been depleted by RNAi are sensitive to genotoxic insult and display decreased SSB repair capacity [5], [13], [14]. Analysis of two different XRCC1-deficient human cell lines revealed that exposure to MMS also leads to an induction of cell cycle checkpoints with a significant delay in S-phase progression [5]. This MMS damage response profile is shared by mouse fibroblasts deficient for either poly(ADP-ribose) polymerase-1 (PARP-1) or DNA polymerase β, proteins that both play important roles in BER [10], [15]. These findings demonstrate the importance of the functionality of base excision and SSB repair in ensuring PF-562271 cell cycle control in the presence of DNA damage. An S-phase cell cycle checkpoint is activated in the presence of DNA damage via an evolutionarily conserved signal transduction pathway whose central components are the checkpoint kinases ataxia-telangectasia mutated (ATM) and ATM- and Rad3-related (ATR). In cells that experience genotoxic stress during replication, activation of these factors triggers the signalling cascades leading to delayed progression through S-phase in order to allow time for DNA repair [16]. Activation depends on the type of DNA damage: ATM is recruited to DNA double-strand breaks (DSBs) induced by agents such as ionizing radiation (IR), whereas ATR is recruited to replication protein A (RPA)-coated single-stranded DNA (ssDNA) that accumulates at stalled replication forks or is generated by processing of initial DNA damage such as single-stranded DNA gaps or UV-induced DNA damage [17], [18], [19], [20]. The involvement of ATM and ATR in the response to MMS-induced DNA damage was established by Barfknecht and Little [21] and Cliby et al. [22], respectively, who reported an enhanced sensitivity of ATM- and ATR-defective cells to methylating agents. Until recently, it was thought that ATM and ATR work independently of one another but it would appear that the two signalling pathways are interconnected. For instance, ATR functions in an ATM- and cell cycle-dependent fashion in DSB repair after IR treatment [23], [24], and replication fork stalling following treatment of cells with UV and hydroxyurea activates ATM in an ATR-dependent fashion [25].