h TDP2 inducible lentiviral particles
- Known as:
- h TDP2 inducible lentiviral beads
- Catalog number:
- LVP601
- Product Quantity:
- 1x107 IFU/ml x 200ul
- Category:
- -
- Supplier:
- GenTarget
- Gene target:
- TDP2 inducible lentiviral particles
Related genes to: h TDP2 inducible lentiviral particles
- Gene:
- TDP2 NIH gene
- Name:
- tyrosyl-DNA phosphodiesterase 2
- Previous symbol:
- TTRAP
- Synonyms:
- -
- Chromosome:
- 6p22.3
- Locus Type:
- gene with protein product
- Date approved:
- 2003-05-02
- Date modifiied:
- 2016-10-05
Related products to: h TDP2 inducible lentiviral particles
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- SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. De novo indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ∼21 bp. The tyrosyl-DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of de novo mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution. - Source: PubMed
Publication date: 2026/07/31
Lukaszewicz AgnieszkaWilson Thomas EKim SoonjoungKeeney ScottJasin Maria - Tyrosyl-DNA phosphodiesterase I (Tdp1) hydrolyzes 3'- and 5'-phosphodiester linked DNA-adducts, including Topoisomerase I- and II-DNA covalent complexes (Topo1cc and Topo2cc). Utilizing the model organism Saccharomyces cerevisiae, which only expresses Tdp1 and does not contain TDP2 orthologs or activity, we investigated the conditions under which Tdp1 processes Topo2(peptide)cc in cells and examined the role of the Tdp1 N-terminal domain in resolving Topo2(peptide)cc. We replaced the transcription activator PDR1 gene with the chimeric pdr1dbd-CYC8 transcription repressor in our strain, resulting in increased sensitivity to etoposide and doxorubicin but not to mitoxantrone. Using Tdp1 catalytic histidine mutants that induce substrate-dependent toxicity, we detected that Tdp1 selectively processes etoposide stabilized Topo2(peptide)cc. In contrast, Tdp1's processing of Topo1cc is drug independent. Moreover, we observed that the yeast SCAN1-like H432R mutant induces a more severe toxic phenotype when processing etoposide-Topo2(peptide)cc than Topo1cc with or without camptothecin. Extrapolating this observation to SCAN1 cerebellar neurons, we hypothesize that the contribution of Tdp1H493R processing of Topo2β(peptide)cc trapped by e.g., oxidative damaged nucleotides, is potentially more substantial towards cerebellar atrophy and compels further investigation. Nonetheless, the observed toxic phenotypes induced by Tdp1 mutants are recessive and suppressed by endogenous wild-type Tdp1 by lowering 5'Tdp1(mutant)cc. Moreover, Tdp1 cannot process etoposide-Topo2cc in cells without its N-terminal domain. This suggests that in cells Tdp1's N-terminal domain plays a critical role in regulating Tdp1 activity potentially by mediating recruitment to the DNA-adduct and/or facilitating accessibility to the phosphodiester linkage within a protein/peptide-DNA complex or stabilizing of the DNA strands related to damaged nucleotide-adducts. - Source: PubMed
Publication date: 2026/03/17
Albertson Victoria MMusani Aasim MBridges Leanna GSegura Isaac Avan Waardenburg Robert C A M - Exonuclease/endonuclease/phosphatase (EEP)-fold hydrolases are canonically monomeric phosphodiesterases exemplified by APE1, DNase I, and TDP2 nucleases. While EEP family domain containing protein 1 (EEPD1) acts in DNA stress responses, its proposed nuclease activities are enigmatic. Here, we integrate hybrid structural methods, evolution, biochemistry, cancer genomics, plus molecular and cell biology to define EEPD1 structure, assembly, and function at stalled DNA replication forks. Results imply EEPD1 surprisingly requires both unique EEP domain dimer and distinctive tandem Helix-hairpin-Helix [(HhH)2] domains to clamp double-stranded (ds) DNA at reversed DNA replication forks for fork protection. Small-angle X-ray Scattering (SAXS), crystal, and cryo-EM structures unveil an unprecedented tryptophan handshake dimer, conserved interface di-Trp-Pro pocket, and adjustable "wrist" enabling an open-closed conformational switch. EEPD1 dimer cooperatively binds complex dsDNA replication fork intermediates but alone lacks nuclease activity due to loss of key EEP catalytic residues during Metazoan evolution and atmospheric oxygen buildup. Instead, EEPD1 prevents nucleolytic degradation of reversed replication forks by MRE11. Furthermore, cancer bioinformatics support oxidative damage-dependent EEPD1 association as a significant modulator of overall patient survival. Collective findings uncover unexpected EEP dimer and fork protection function in clamping, not cleaving, reversed replication forks for metazoan oxidative stress responses controlling genome stability and cancer outcomes. - Source: PubMed
Shen RunzeSarker Altaf HChen YueLiu MinRoy SunetraArvai Andrew SBacolla AlbinoAhmed ZamalKatsonis PanagiotisHammel MichalKuraoka IsaoTsai Miaw-SheueIrie CorydonWebb LukasLichtarge OlivierTsai Chi-LinTsutakawa Susan ESchlacher KatharinaTainer John A - Dedifferentiated liposarcoma (DDLPS) is a rare cancer defined by amplification of mouse double minute 2 (MDM2) and cyclin-dependent kinase (CDK) 4. Conventional chemotherapy (doxorubicin) and targeted inhibition of MDM2 and CDK4 show sporadic responses, but most tumors display primary resistance. In this study, we used an unbiased approach to identify therapeutic strategies sensitizing to these DDLPS therapies. Three parallel genome-wide CRISPR-Cas9 knockout screens were conducted in DDLPS cells to sensitize to palbociclib (CDK4 inhibitor), nutlin-3a (MDM2 inhibitor), or doxorubicin. Top screen hits were validated and characterized in both in vitro and in vivo models, whereas clinical data were used to corroborate molecular findings. Inactivation of genes related to G1-S transition (CDK2, CKS1B, E2F3, and CCNE1) and non-homologous end joining (NHEJ; TDP2, PRKDC, and XRCC4) enhanced sensitivity to palbociclib and doxorubicin, respectively. Genetic perturbation of TDP2 or pharmacologic inhibition of DNA-dependent kinase catalytic subunit (DNA-PKcs) using peposertib synergized with prolonged administration of low-dose doxorubicin to induce cell-cycle arrest and senescence, and subsequent senolytic treatment with Bcl-2 inhibitor navitoclax triggered senescent cells to undergo apoptosis. Despite the amplification of MDM2, senescence was mediated by p53. Consistently, The Cancer Genome Atlas (TCGA) and DepMap data suggested p53 activity in DDLPS. These findings provide a rationale for targeting the NHEJ pathway to enhance the efficacy of low-dose doxorubicin in DDLPS, highlighting a potential therapeutic strategy exploiting p53-mediated cell-cycle arrest and senescence. Furthermore, this study provides evidence that baseline p53 activity is preserved in DDLPS despite MDM2 amplification. - Source: PubMed
Jalving ThijsDufau CarineSimon Nieto JuanD'Empaire Altimari Daniela Mvan Hal-van Veen Susan EJin Elisabeth HVisser Nils LVan Boven Hester Hvan der Graaf Winette T Avan Houdt Winan JPeeper Daniel S - SPO11 forms hundreds of double-strand breaks (DSBs) to initiate meiotic recombination that is normally error-free. However, SPO11 activity can be mutagenic when one chromatid incurs closely spaced DSBs (double cuts), especially when DSBs are dysregulated by loss of the ATM kinase. indels and structural variants can arise via end joining at double cuts within a single hotspot (microdeletions) or at adjacent hotspots separated by at least 30 kb, as we now show, sometimes accompanied by ectopic insertions of double-cut fragments. Here, we investigate how meiotic DSB end processing influences end joining. In MRE11-deficient mouse spermatocytes, which do not resect their DSBs, deletions at double cuts occur readily, with end-joining breakpoint profiles closely matching SPO11 DSB profiles. Microdeletions suggest that two DSBs can be as close as ~21 bp. The tyrosyl DNA phosphodiesterase TDP2 contributes to both deletion formation and ectopic insertion of double-cut fragments, presumably by removing SPO11 from DNA ends prior to joining. Finally, observations suggest a cooperative role for MRE11 and ATM in locally regulating DSB distributions. Our findings provide insight into the mechanism of mutation origin, emphasizing the role of meiotic DSBs in shaping genome evolution. - Source: PubMed
Publication date: 2026/02/15
Lukaszewicz AgnieszkaWilson Thomas EKim SoonjoungKeeney ScottJasin Maria