Academic literature on the topic 'TDPX2'
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Journal articles on the topic "TDPX2"
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Schellenberg, Matthew J., C. Denise Appel, Amanda A. Riccio, et al. "Ubiquitin stimulated reversal of topoisomerase 2 DNA-protein crosslinks by TDP2." Nucleic Acids Research 48, no. 11 (2020): 6310–25. http://dx.doi.org/10.1093/nar/gkaa318.
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Abstract Tyrosyl-DNA phosphodiesterase 2 (TDP2) reverses Topoisomerase 2 DNA–protein crosslinks (TOP2-DPCs) in a direct-reversal pathway licensed by ZATTZNF451 SUMO2 E3 ligase and SUMOylation of TOP2. TDP2 also binds ubiquitin (Ub), but how Ub regulates TDP2 functions is unknown. Here, we show that TDP2 co-purifies with K63 and K27 poly-Ubiquitinated cellular proteins independently of, and separately from SUMOylated TOP2 complexes. Poly-ubiquitin chains of ≥ Ub3 stimulate TDP2 catalytic activity in nuclear extracts and enhance TDP2 binding of DNA–protein crosslinks in vitro. X-ray crystal structures and small-angle X-ray scattering analysis of TDP2-Ub complexes reveal that the TDP2 UBA domain binds K63-Ub3 in a 1:1 stoichiometric complex that relieves a UBA-regulated autoinhibitory state of TDP2. Our data indicates that that poly-Ub regulates TDP2-catalyzed TOP2-DPC removal, and TDP2 single nucleotide polymorphisms can disrupt the TDP2-Ubiquitin interface.
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Hornyak, Peter, Trevor Askwith, Sarah Walker, et al. "Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2." Biochemical Journal 473, no. 13 (2016): 1869–79. http://dx.doi.org/10.1042/bcj20160180.
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Tyrosyl-DNA phosphodiesterase 2 (TDP2) is a 5′-tyrosyl DNA phosphodiesterase important for the repair of DNA adducts generated by non-productive (abortive) activity of topoisomerase II (TOP2). TDP2 facilitates therapeutic resistance to topoisomerase poisons, which are widely used in the treatment of a range of cancer types. Consequently, TDP2 is an interesting target for the development of small molecule inhibitors that could restore sensitivity to topoisomerase-directed therapies. Previous studies identified a class of deazaflavin-based molecules that showed inhibitory activity against TDP2 at therapeutically useful concentrations, but their mode of action was uncertain. We have confirmed that the deazaflavin series inhibits TDP2 enzyme activity in a fluorescence-based assay, suitable for high-throughput screen (HTS)-screening. We have gone on to determine crystal structures of these compounds bound to a ‘humanized’ form of murine TDP2. The structures reveal their novel mode of action as competitive ligands for the binding site of an incoming DNA substrate, and point the way to generating novel and potent inhibitors of TDP2.
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Lee, Ka, Rebecca Swan, Zbyslaw Sondka, Kay Padget, Ian Cowell, and Caroline Austin. "Effect of TDP2 on the Level of TOP2-DNA Complexes and SUMOylated TOP2-DNA Complexes." International Journal of Molecular Sciences 19, no. 7 (2018): 2056. http://dx.doi.org/10.3390/ijms19072056.
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DNA topoisomerase II (TOP2) activity involves a normally transient double-strand break intermediate in which the enzyme is coupled to DNA via a 5′-phosphotyrosyl bond. However, etoposide and other topoisomerase drugs poison the enzyme by stabilising this enzyme-bridged break, resulting in the accumulation of TOP2-DNA covalent complexes with cytotoxic consequences. The phosphotyrosyl diesterase TDP2 appears to be required for efficient repair of this unusual type of DNA damage and can remove 5′-tyrosine adducts from a double-stranded oligonucleotide substrate. Here, we adapt the trapped in agarose DNA immunostaining (TARDIS) assay to investigate the role of TDP2 in the removal of TOP2-DNA complexes in vitro and in cells. We report that TDP2 alone does not remove TOP2-DNA complexes from genomic DNA in vitro and that depletion of TDP2 in cells does not slow the removal of TOP2-DNA complexes. Thus, if TDP2 is involved in repairing TOP2 adducts, there must be one or more prior steps in which the protein-DNA complex is processed before TDP2 removes the remaining 5′ tyrosine DNA adducts. While this is partly achieved through the degradation of TOP2 adducts by the proteasome, a proteasome-independent mechanism has also been described involving the SUMOylation of TOP2 by the ZATT E3 SUMO ligase. The TARDIS assay was also adapted to measure the effect of TDP2 knockdown on levels of SUMOylated TOP2-DNA complexes, which together with levels of double strand breaks were unaffected in K562 cells following etoposide exposure and proteasomal inhibition.
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Schellenberg, Matthew J., Jenna Ariel Lieberman, Andrés Herrero-Ruiz, et al. "ZATT (ZNF451)–mediated resolution of topoisomerase 2 DNA-protein cross-links." Science 357, no. 6358 (2017): 1412–16. http://dx.doi.org/10.1126/science.aam6468.
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Topoisomerase 2 (TOP2) DNA transactions proceed via formation of the TOP2 cleavage complex (TOP2cc), a covalent enzyme-DNA reaction intermediate that is vulnerable to trapping by potent anticancer TOP2 drugs. How genotoxic TOP2 DNA-protein cross-links are resolved is unclear. We found that the SUMO (small ubiquitin-related modifier) ligase ZATT (ZNF451) is a multifunctional DNA repair factor that controls cellular responses to TOP2 damage. ZATT binding to TOP2cc facilitates a proteasome-independent tyrosyl-DNA phosphodiesterase 2 (TDP2) hydrolase activity on stalled TOP2cc. The ZATT SUMO ligase activity further promotes TDP2 interactions with SUMOylated TOP2, regulating efficient TDP2 recruitment through a “split-SIM” SUMO2 engagement platform. These findings uncover a ZATT-TDP2–catalyzed and SUMO2-modulated pathway for direct resolution of TOP2cc.
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Huang, Shar-yin Naomi, and Yves Pommier. "Mammalian Tyrosyl-DNA Phosphodiesterases in the Context of Mitochondrial DNA Repair." International Journal of Molecular Sciences 20, no. 12 (2019): 3015. http://dx.doi.org/10.3390/ijms20123015.
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Mammalian mitochondria contain four topoisomerases encoded in the nuclear genome: TOP1MT, TOP2α, TOP2β, and TOP3α. They also contain the two known tyrosyl-DNA phosphodiesterases (TDPs): TDP1 and TDP2, including a specific TDP2S isoform. Both TDP1 and TDP2 excise abortive topoisomerase cleavage complexes (TOPccs), yet their molecular structures and mechanisms are different. TDP1 is present across eukaryotes, from yeasts to humans and belongs to the phospholipase D family. It functions without a metal cofactor and has a broad activity range, as it also serves to cleanse blocking 3′-DNA ends bearing phosphoglycolate, deoxyribose phosphate, nucleoside, nucleoside analogs (zidovudine), abasic moieties, and with a lower efficiency, TOP2ccs. Found in higher vertebrates, TDP2 is absent in yeast where TDP1 appears to perform its functions. TDP2 belongs to the exonuclease/endonuclease/phosphodiesterase family and requires magnesium as a cofactor to excise TOP2ccs, and it also excises TOP1ccs, albeit with a lower efficiency. Here, we review TDP1 and TDP2 in the context of mitochondrial DNA repair and discuss potential new research areas centered on the mitochondrial TDPs.
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Zakharenko, Alexandra L., Nadezhda S. Dyrkheeva, Olga A. Luzina, et al. "Usnic Acid Derivatives Inhibit DNA Repair Enzymes Tyrosyl-DNA Phosphodiesterases 1 and 2 and Act as Potential Anticancer Agents." Genes 14, no. 10 (2023): 1931. http://dx.doi.org/10.3390/genes14101931.
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Tyrosyl-DNA phosphodiesterase 1 and 2 (Tdp1 and Tdp2) are DNA repair enzymes that repair DNA damage caused by various agents, including anticancer drugs. Thus, these enzymes resist anticancer therapy and could be the reason for resistance to such widely used drugs such as topotecan and etoposide. In the present work, we found compounds capable of inhibiting both enzymes among derivatives of (−)-usnic acid. Both (+)- and (−)-enantiomers of compounds act equally effectively against Tdp1 with IC50 values in the range of 0.02–0.2 μM; only (−)-enantiomers inhibited Tdp2 with IC50 values in the range of 6–9 μM. Surprisingly, the compounds protect HEK293FT wild type cells from the cytotoxic effect of etoposide (CC50 3.0–3.9 μM in the presence of compounds and 2.4 μM the presence of DMSO) but potentiate it against Tdp2 knockout cells (CC50 1.2–1.6 μM in the presence of compounds against 2.3 μM in the presence of DMSO). We assume that the sensitizing effect of the compounds in the absence of Tdp2 is associated with the effective inhibition of Tdp1, which could take over the functions of Tdp2.
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Park, Jeong-Min, Huimin Zhang, Litong Nie, et al. "Genome-Wide CRISPR Screens Reveal ZATT as a Synthetic Lethal Target of TOP2-Poison Etoposide That Can Act in a TDP2-Independent Pathway." International Journal of Molecular Sciences 24, no. 7 (2023): 6545. http://dx.doi.org/10.3390/ijms24076545.
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Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2–DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5′-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens revealed that ZATT also has a TDP2-independent role in promoting cell survival following ETO treatment. ZATT KO cells showed relatively higher ETO sensitivity than TDP2-KO cells, and ZATT/TDP2 DKO cells displayed additive hypersensitivity to ETO treatment. The study using a series of deletion mutants of ZATT determined that the N-terminal 1–168 residues of ZATT are required for interaction with TOP2 and this interaction is critical to ETO sensitivity. Moreover, depletion of ZATT resulted in accelerated TOP2 degradation after ETO or cycloheximide (CHX) treatment, suggesting that ZATT may increase TOP2 stability and likely participate in TOP2 turnover. Taken together, this study suggests that ZATT is a critical determinant that dictates responses to ETO treatment and targeting. ZATT is a promising strategy to increase ETO efficacy for cancer therapy.
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Holmes, Autumn C., Guido Zagnoli-Vieira, Keith W. Caldecott, and Bert L. Semler. "Effects of TDP2/VPg Unlinkase Activity on Picornavirus Infections Downstream of Virus Translation." Viruses 12, no. 2 (2020): 166. http://dx.doi.org/10.3390/v12020166.
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In this study, we characterized the role of host cell protein tyrosyl-DNA phosphodiesterase 2 (TDP2) activity, also known as VPg unlinkase, in picornavirus infections in a human cell model of infection. TDP2/VPg unlinkase is used by picornaviruses to remove the small polypeptide, VPg (Virus Protein genome-linked, the primer for viral RNA synthesis), from virus genomic RNA. We utilized a CRISPR/Cas-9-generated TDP2 knock out (KO) human retinal pigment epithelial-1 (hRPE-1) cell line, in addition to the wild type (WT) counterpart for our studies. We determined that in the absence of TDP2, virus growth kinetics for two enteroviruses (poliovirus and coxsackievirus B3) were delayed by about 2 h. Virus titers were reduced by ~2 log10 units for poliovirus and 0.5 log10 units for coxsackievirus at 4 hours post-infection (hpi), and by ~1 log10 unit at 6 hpi for poliovirus. However, virus titers were nearly indistinguishable from those of control cells by the end of the infectious cycle. We determined that this was not the result of an alternative source of VPg unlinkase activity being activated in the absence of TPD2 at late times of infection. Viral protein production in TDP2 KO cells was also substantially reduced at 4 hpi for poliovirus infection, consistent with the observed growth kinetics delay, but reached normal levels by 6 hpi. Interestingly, this result differs somewhat from what has been reported previously for the TDP2 KO mouse cell model, suggesting that either cell type or species-specific differences might be playing a role in the observed phenotype. We also determined that catalytically inactive TDP2 does not rescue the growth defect, confirming that TDP2 5′ phosphodiesterase activity is required for efficient virus replication. Importantly, we show for the first time that polysomes can assemble efficiently on VPg-linked RNA after the initial round of translation in a cell culture model, but both positive and negative strand RNA production is impaired in the absence of TDP2 at mid-times of infection, indicating that the presence of VPg on the viral RNA affects a step in the replication cycle downstream of translation (e.g., RNA synthesis). In agreement with this conclusion, we found that double-stranded RNA production (a marker of viral RNA synthesis) is delayed in TDP2 KO RPE-1 cells. Moreover, we show that premature encapsidation of nascent, VPg-linked RNA is not responsible for the observed virus growth defect. Our studies provide the first lines of evidence to suggest that either negative- or positive-strand RNA synthesis (or both) is a likely candidate for the step that requires the removal of VPg from the RNA for an enterovirus infection to proceed efficiently.
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Kan, Chau Ming, Xiao Meng Pei, Simon Siu Man Ng, et al. "Validation of Prognostic Circulating Cell-Free RNA Biomarkers HPGD, PACS1, and TDP2 in Colorectal Cancer Through TaqMan qPCR and Correlation Analysis." Current Issues in Molecular Biology 47, no. 7 (2025): 508. https://doi.org/10.3390/cimb47070508.
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Circulating cell-free RNAs (cfRNAs) have emerged as promising non-invasive biomarkers for colorectal cancer (CRC), offering insights into the disease’s prognosis. This study investigates the prognostic significance of the specific cfRNA biomarkers HPGD, PACS1, and TDP2 by employing the Taqman quantitative PCR (qPCR) to evaluate their expression levels in a cohort of 52 CRC patients. The methodology involved a robust statistical analysis to assess correlations between cfRNA levels and clinical parameters, including survival rates and recurrence incidences. Findings revealed a significant upregulation in the expression of HPGD and PACS1, while TDP2 displayed varying results, indicating a complex role in disease dynamics. Notably, lower expression levels of HPGD were associated with reduced survival, suggesting its potential as a negative prognostic indicator. Conversely, TDP2 levels correlated strongly with increased risks of recurrence, highlighting its clinical relevance in monitoring disease progression. Overall, this study elucidates the intricate interplay between these cfRNAs in the CRC prognosis. The results advocate for further exploratory studies to validate PACS1’s potential as a prognostic marker and reinforce the clinical significance of HPGD and TDP2 in the context of CRC management, positioning them as vital elements in the landscape of molecular oncology.
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Filimonov, Aleksandr S., Marina A. Mikhailova, Nadezhda S. Dyrkheeva, et al. "Sulfide, Sulfoxide, and Sulfone Derivatives of Usnic Acid as Inhibitors of Human TDP1 and TDP2 Enzymes." Chemistry 6, no. 6 (2024): 1658–79. https://doi.org/10.3390/chemistry6060101.
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Tyrosyl-DNA phosphodiesterases 1 and 2 (TDP1 and TDP2) are important DNA repair enzymes that remove various adducts from the 3′- and 5′-ends of DNA, respectively. The suppression of the activity of these enzymes is considered as a promising adjuvant therapy for oncological diseases in combination with topoisomerase inhibitors. The simultaneous inhibition of TDP1 and TDP2 may result in greater antitumor effects, as these enzymes can mimic each other’s functions. We have previously shown that usnic acid-based sulfides can act as dual inhibitors, with TDP1 activity in the low micromolar range and their TDP2 at 1 mM. The oxidation of their sulfide moieties to sulfoxides led to an order of magnitude decrease in their cytotoxicity potential, while their TDP1 and TDP2 activity was preserved. In this work, we synthesized new series of usnic acid-based sulfides and their oxidized analogues, i.e., sulfoxides and sulfones, to systematically study these irregularities. The new compounds inhibit TDP1 with IC50 values (the concentration of inhibitor required to reduce enzyme activity by half) in the 0.33–25 μM range. Most sulfides and some sulfoxides and sulfones inhibit TDP2 with an IC50 = 138−421 μM. In addition, the most active compounds synergized (×4) with topotecan on the HeLa cell line as well as causing dose-dependent DNA damage, as confirmed by Comet assay. Sulfides with the 6-methylbenzoimidazol-2-yl substituent (8f, IC50 = 0.33/138 μM, TDP1/2) and sulfones containing a pyridine-2-yl fragment (12k, IC50 = 2/228 μM, TDP1/2) are the most potent derivatives and, therefore, are promising for further development.
Dissertations / Theses on the topic "TDPX2"
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Mahmud, Md Rasel Al. "TDP2 suppresses genomic instability induced by androgen in the epithelial cells of prostate glands." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263551.
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付記する学位プログラム名: 充実した健康長寿社会を築く総合医療開発リーダー育成プログラム<br>京都大学<br>新制・課程博士<br>博士(医学)<br>甲第23090号<br>医博第4717号<br>京都大学大学院医学研究科医学専攻<br>(主査)教授 篠原 隆司, 教授 小川 修, 教授 溝脇 尚志<br>学位規則第4条第1項該当<br>Doctor of Medical Science<br>Kyoto University<br>DFAM
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Ntai, Ioanna. "TDP2 as a biomarker of sensitivity to TOP2 targeting agents and as a novel therapeutic target." Thesis, University of Sussex, 2017. http://sro.sussex.ac.uk/id/eprint/68291/.
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TDP2, a DNA phosphodiesterase that removes trapped topoisomerase 2 (TOP2) from 5'-DNA termini, is required for efficient repair of TOP2-induced DNA double-strand breaks (DSBs). Cellular depletion of TDP2 was shown to result in a substantially increased sensitivity to TOP2-induced DSBs and TOP2 poisons, such as etoposide, in various types of human cancer cell lines. In addition, over-expression of TDP2 has been shown to increase resistance to etoposide. Recent data suggest that expression levels of TDP2 vary greatly in different cancer cell lines. However, there are no reported studies addressing the possible role of TDP2 as a clinical predictor of anti-cancer therapy outcome, or wider studies correlating TDP2 over-expression with resistance to TOP2 poisons. TDP2 has the potential to be a good target for pharmacological inhibition potentially increasing tumour sensitivity to TOP2 poisons, particularly those that develop resistance during the course of treatment. There is already a lot of interest in the development of TDP2 inhibitors and the in vitro results are very promising with many possible small molecule inhibitors showing selectiveness in their target. In my thesis I aim to further establish the range of TDP2 and TOP2 mRNA and protein levels in a panel of lung and breast cancer cell lines. In addition, I will explore the possibility of a correlation between TDP2 protein levels or TOP2/TDP2 protein ratios and sensitivity to the TOP2 poison etoposide. This likely complex relationship will be further defined by possible mutation effects based on available literature and studies for the cancer cell lines accessible for this project. Furthermore, as etoposide has been tested in clinical trials not only alone but also in combination with other treatments, I aim to include other accessible drugs, either currently in use for cancer treatment or at a promising clinical trial stage, such as estradiol and PARP1 inhibitors. There is a recent model, which suggests that induction of transcriptional programs by stimulating breast cancer cells with estrogens, or prostate cancer cells with androgens, can involve the formation of TOP2B mediated DSBs and the recruitment of DSB repair proteins. TOP2B is believed to be recruited with the estrogen/androgen receptor to regulatory sites on target genes. It is hypothesized that the formation of these DSBs by TOP2B could also be exploited therapeutically. In my thesis I aim to utilise a combination treatment that will first induce transcription with estradiol in breast cancer cells, which will cause transient TOP2B-mediated DSBs, and then transform those breaks into abortive breaks with etoposide. Cells will then be overwhelmed with DSBs and apoptosis will be promoted. This will also be explored in TDP2-depleted MCF7 breast cancer cells. Such a strategy could possibly find particular use in hormone dependent cancers, where other types of treatment have failed.
Conference papers on the topic "TDPX2"
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Li, Chunyang, Fadlo R. Khuri, Shi-yong Sun, and Runzhao Li. "Abstract 2207: SUMOylation of EAPII/TTRAP/TDP2 modulates its function." In Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.am2012-2207.
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Jordan, Allan M., Paul Depledge, Nicola Hamilton, et al. "Abstract 3324: The discovery and optimisation of small-molecule inhibitors of human 5’-tyrosyl DNA phosphodiesterase (Tdp2)." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-3324.
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Bezerra, Rebeka Ellen de Alencar, Agda Yasmim Ferreira Correia, Héryka Wanessa do Nascimento Rolim, et al. "Importance of individualized diagnosis and treatment in refractory epilepsy associated with intellectual disability." In XIII Congresso Paulista de Neurologia. Zeppelini Editorial e Comunicação, 2021. http://dx.doi.org/10.5327/1516-3180.050.
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Background: Epilepsy is a complex neurological disorder, that affects 0.5 to 1% of the population, with a diversified etiology, but with emphasis on its relation with genetics. Despite there are several therapies to treat it, in some cases, this variety is still insuficiente, featuring refractory epilepsy, frequent in people with intelectual disabilities (ID). Objectives: To analyze the scientific production about refractory epilepsy and ID. Methods: Integrative literature review that searched for international articles in the Virtual Health Library (VHL), using the keywords “Intellectual disability” AND “Refractory epilepsy” with the filter: “full text”. Results: From the 27 articles found, 2 were excluded for escaping the theme, having 25 articles as a final corpus and 2 thematic axes identified: (I) Genetic aspects related to ID and refractory epilepsy and (II) Therapeutic interventions in these patients. According to studies, refractory epilepsy in people with ID is related to mutations in some genes, such as: PCDH19, FMR1, TDP2, GABRB2 and SLC9A6. As for therapies for these patients, drugs such as stiripentol, lacosamide and benzodiazepines have been used, in addition to other interventions such as vagus nerve therapies, responsive neural stimulation, ketogenic diet, immunotherapy and resection surgery. Conclusions: The ID association with refractory epilepsy is strongly linked to genetic mutations, being essencial the genetic diagnosid to individualize the treatment and overcome insuficiente therapies for this epilepsy, especially in patients with associated ID, who tend to have a reduced life quality, having as primary objective the improvement of it.