Only in Titles

Search results for: RAD18

paperclip

#36333305   2022/11/04 To Up

Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

Embryonic development is dictated by tight regulation of DNA replication, cell division and differentiation. Mutations in DNA repair and replication genes disrupt this equilibrium, giving rise to neurodevelopmental disease characterized by microcephaly, short stature and chromosomal breakage. Here, we identify biallelic variants in two components of the RAD18-SLF1/2-SMC5/6 genome stability pathway, SLF2 and SMC5, in 11 patients with microcephaly, short stature, cardiac abnormalities and anemia. Patient-derived cells exhibit a unique chromosomal instability phenotype consisting of segmented and dicentric chromosomes with mosaic variegated hyperploidy. To signify the importance of these segmented chromosomes, we have named this disorder Atelís (meaning - incomplete) Syndrome. Analysis of Atelís Syndrome cells reveals elevated levels of replication stress, partly due to a reduced ability to replicate through G-quadruplex DNA structures, and also loss of sister chromatid cohesion. Together, these data strengthen the functional link between SLF2 and the SMC5/6 complex, highlighting a distinct role for this pathway in maintaining genome stability.
Laura J Grange, John J Reynolds, Farid Ullah, Bertrand Isidor, Robert F Shearer, Xenia Latypova, Ryan M Baxley, Antony W Oliver, Anil Ganesh, Sophie L Cooke, Satpal S Jhujh, Gavin S McNee, Robert Hollingworth, Martin R Higgs, Toyoaki Natsume, Tahir Khan, Gabriel Á Martos-Moreno, Sharon Chupp, Christopher G Mathew, David Parry, Michael A Simpson, Nahid Nahavandi, Zafer Yüksel, Mojgan Drasdo, Anja Kron, Petra Vogt, Annemarie Jonasson, Saad Ahmed Seth, Claudia Gonzaga-Jauregui, Karlla W Brigatti, Alexander P A Stegmann, Masato Kanemaki, Dragana Josifova, Yuri Uchiyama, Yukiko Oh, Akira Morimoto, Hitoshi Osaka, Zineb Ammous, Jesús Argente, Naomichi Matsumoto, Constance T R M Stumpel, Alexander M R Taylor, Andrew P Jackson, Anja-Katrin Bielinsky, Niels Mailand, Cedric Le Caignec, Erica E Davis, Grant S Stewart

2233 related Products with: Pathogenic variants in SLF2 and SMC5 cause segmented chromosomes and mosaic variegated hyperploidy.

100 mg1000 tests100ug50 ug 25 mg10 mg100ug500 MG25 mg96T100ul100ug

Related Pathways

paperclip

#36319861   2022/11/01 To Up

Genetic analysis of DNA-damage tolerance pathways in Arabidopsis.

Genetic analysis revealed a two-branch DNA-damage tolerance mechanism in Arabidopsis, namely translesion DNA synthesis and error-free lesion bypass, represented by Rev3 and Rad5a-Uev1C/D, respectively. DNA-damage tolerance (DDT) is a mechanism by which cells complete replication in the presence of replication-blocking lesions. In budding yeast, DDT is achieved through Rad6-Rad18-mediated monoubiquitination of proliferating cell nuclear antigen (PCNA), which promotes translesion DNA synthesis (TLS) and is followed by Ubc13-Mms2-Rad5 mediated K63-linked PCNA polyubiquitination that promotes error-free lesion bypass. Arabidopsis and other known plant genomes contain all of the above homologous genes except RAD18, and whether plants possess an intact DDT mechanism is unclear. In this study, we created Arabidopsis UEV1 (homologous to yeast MMS2) gene mutations and obtained two sets of double mutant lines Atuev1ab and Atuev1cd. It turned out that the Atuev1cd, but not the Atuev1ab mutant, was sensitive to DNA damage. Genetic analyses revealed that AtUEV1C/D and AtRAD5a function in the same pathway, while TLS represented by AtREV3 functions in a separate pathway in response to replication-blocking lesions. Furthermore, unlike budding yeast RAD5 that also functions in the TLS pathway, AtRAD5a is not required for TLS. Observations in this study collectively establish a two-branch DDT model in plants with similarity to and difference from the yeast DDT.
Linxiao Wang, Kun Yang, Qiuheng Wang, Wei Xiao

1610 related Products with: Genetic analysis of DNA-damage tolerance pathways in Arabidopsis.

96 assays20000 Units25mg100ug100ug Lyophilized100ug1 g1 Set100 μg

Related Pathways

paperclip

#36228090   2022/10/12 To Up

Ubiquitinated PCNA drives USP1 synthetic lethality in cancer.

CRISPR Cas9-based screening is a powerful approach for identifying and characterizing novel drug targets. Here, we elucidate the synthetic lethal mechanism of deubiquitinating enzyme USP1 in cancers with underlying DNA damage vulnerabilities, specifically BRCA1/2 mutant tumors and a subset of BRCA1/2 wild-type (WT) tumors. In sensitive cells, pharmacological inhibition of USP1 leads to decreased DNA synthesis concomitant with S-phase-specific DNA damage. Genome-wide CRISPR-Cas9 screens identify RAD18 and UBE2K, which promote PCNA mono- and polyubiquitination respectively, as mediators of USP1 dependency. The accumulation of mono- and polyubiquitinated PCNA following USP1 inhibition is associated with reduced PCNA protein levels. Ectopic expression of WT or ubiquitin-dead K164R PCNA reverses USP1 inhibitor sensitivity. Our results demonstrate, for the first time, that USP1 dependency hinges on the aberrant processing of mono- and polyubiquitinated PCNA. Moreover, this mechanism of USP1 dependency extends beyond BRCA1/2 mutant tumors to selected BRCA1/2 WT cancer cell lines enriched in ovarian and lung lineages. We further show PARP and USP1 inhibition are strongly synergistic in BRCA1/2 mutant tumors. We postulate USP1 dependency unveils a previously uncharacterized vulnerability linked to post-translational modifications of PCNA. Taken together, USP1 inhibition may represent a novel therapeutic strategy for BRCA1/2 mutant tumors and a subset of BRCA1/2 WT tumors.
Antoine Simoneau, Justin L Engel, Madhavi Bandi, Katherine Lazarides, Shangtao Liu, Samuel R Meier, Ashley H Choi, Hongxiang Zhang, Binzhang Shen, Lauren Martires, Deepali Gotur, Truc V Pham, Fang Li, Lina Gu, Shanzhong Gong, Minjie Zhang, Erik Wilker, Xuewen Pan, Douglas A Whittington, Scott Throner, John P Maxwell, Yingnan Chen, Yi Yu, Alan Huang, Jannik N Andersen, Tianshu Feng

2917 related Products with: Ubiquitinated PCNA drives USP1 synthetic lethality in cancer.



Related Pathways

paperclip

#36152406   2022/09/21 To Up

Molecular markers related to patient outcome in patients with IDH-mutant astrocytomas grade 2 to 4: A systematic review.

Grading and classification of IDH-mutant astrocytomas has shifted from solely histology towards histology combined with molecular diagnostics. In this systematic review, we give an overview of all currently known clinically relevant molecular markers within IDH-mutant astrocytomas grade 2 to 4.
C Mircea S Tesileanu, Wies R Vallentgoed, Pim J French, Martin J van den Bent

1362 related Products with: Molecular markers related to patient outcome in patients with IDH-mutant astrocytomas grade 2 to 4: A systematic review.

100 μg100 mg25 100 250 m Pcs Per Pack100 mg

Related Pathways

paperclip

#36126360   2022/09/09 To Up

Identification of BRIP1, NSMCE2, ANAPC7, RAD18 and TTL from chromosome segregation gene set associated with hepatocellular carcinoma.

Hepatocellular carcinoma is one of the most frequent cancers with high mortality rate worldwide.
Ceren Sucularli

1601 related Products with: Identification of BRIP1, NSMCE2, ANAPC7, RAD18 and TTL from chromosome segregation gene set associated with hepatocellular carcinoma.

300 units

Related Pathways

    No related Items
paperclip

#36087615   2022/09/08 To Up

Impacts of arsenic on Rad18 and translesion synthesis.

Arsenite interferes with DNA repair protein function resulting in the retention of UV-induced DNA damage. Accumulated DNA damage promotes replication stress which is bypassed by DNA damage tolerance pathways such as translesion synthesis (TLS). Rad18 is an essential factor in initiating TLS through PCNA monoubiquitination and contains two functionally and structurally distinct zinc fingers that are potential targets for arsenite binding. Arsenite treatment displaced zinc from endogenous Rad18 protein and mass spectrometry analysis revealed arsenite binding to both the Rad18 RING finger and UBZ domains. Consequently, arsenite inhibited Rad18 RING finger dependent PCNA monoubiquitination and polymerase eta recruitment to DNA damage in UV exposed keratinocytes, both of which enhance the bypass of cyclobutane pyrimidine dimers during replication. Further analysis demonstrated multiple effects of arsenite, including the reduction in nuclear localization and UV-induced chromatin recruitment of Rad18 and its binding partner Rad6, which may also negatively impact TLS initiation. Arsenite and Rad18 knockdown in UV exposed keratinocytes significantly increased markers of replication stress and DNA strand breaks to a similar degree, suggesting arsenite mediates its effects through Rad18. Comet assay analysis confirmed an increase in both UV-induced single-stranded DNA and DNA double-strand breaks in arsenite treated keratinocytes compared to UV alone. Altogether, this study supports a mechanism by which arsenite inhibits TLS through the altered activity and regulation of Rad18. Arsenite elevated the levels of UV-induced replication stress and consequently, single-stranded DNA gaps and DNA double-strand breaks. These potentially mutagenic outcomes support a role for TLS in the cocarcinogenicity of arsenite.
L B Volk, K L Cooper, T Jiang, M L Paffett, L G Hudson

2385 related Products with: Impacts of arsenic on Rad18 and translesion synthesis.

1 g 100ul1,000 tests100ul1 mg 25 ml 1000 tests200 100ug

Related Pathways

paperclip

#35895872   // To Up

AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer.

Anticancer therapies have been limited by the emergence of mutations and other adaptations. In bacteria, antibiotics activate the SOS response, which mobilizes error-prone factors that allow for continuous replication at the cost of mutagenesis. We investigated whether the treatment of lung cancer with EGFR inhibitors (EGFRi) similarly engages hypermutators. In cycling drug-tolerant persister (DTP) cells and in EGFRi-treated patients presenting residual disease, we observed upregulation of GAS6, whereas ablation of GAS6's receptor, AXL, eradicated resistance. Reciprocally, AXL overexpression enhanced DTP survival and accelerated the emergence of T790M, an EGFR mutation typical to resistant cells. Mechanistically, AXL induces low-fidelity DNA polymerases and activates their organizer, RAD18, by promoting neddylation. Metabolomics uncovered another hypermutator, AXL-driven activation of MYC, and increased purine synthesis that is unbalanced by pyrimidines. Aligning anti-AXL combination treatments with the transition from DTPs to resistant cells cured patient-derived xenografts. Hence, similar to bacteria, tumors tolerate therapy by engaging pharmacologically targetable endogenous mutators.
Ashish Noronha, Nishanth Belugali Nataraj, Joo Sang Lee, Benny Zhitomirsky, Yaara Oren, Sara Oster, Moshit Lindzen, Saptaparna Mukherjee, Rainer Will, Soma Ghosh, Arturo Simoni-Nieves, Aakanksha Verma, Rishita Chatterjee, Simone Borgoni, Welles Robinson, Sanju Sinha, Alexander Brandis, D Lucas Kerr, Wei Wu, Arunachalam Sekar, Suvendu Giri, Youngmin Chung, Diana Drago-Garcia, Brian P Danysh, Mattia Lauriola, Michelangelo Fiorentino, Andrea Ardizzoni, Moshe Oren, Collin M Blakely, Jideofor Ezike, Stefan Wiemann, Laxmi Parida, Trever G Bivona, Rami I Aqeilan, Joan S Brugge, Aviv Regev, Gad Getz, Eytan Ruppin, Yosef Yarden

2428 related Products with: AXL and Error-Prone DNA Replication Confer Drug Resistance and Offer Strategies to Treat EGFR-Mutant Lung Cancer.

10 mg100ul500 mg50 ug 25 mg 5 G

Related Pathways

paperclip

#35849344   // To Up

LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms.

Sustaining DNA damage response (DDR) signalling via retention of DDR factors at damaged sites is important for transmitting damage-sensing and repair signals. Herein, we found that DNA damage provoked the association of ribosomes with IRES region in lncRNA CTBP1-DT, which overcame the negative effect of upstream open reading frames (uORFs), and elicited the novel microprotein DNA damage-upregulated protein (DDUP) translation via a cap-independent translation mechanism. Activated ATR kinase-mediated phosphorylation of DDUP induced a drastic 'dense-to-loose' conformational change, which sustained the RAD18/RAD51C and RAD18/PCNA complex at damaged sites and initiated RAD51C-mediated homologous recombination and PCNA-mediated post-replication repair mechanisms. Importantly, treatment with ATR inhibitor abolished the effect of DDUP on chromatin retention of RAD51C and PCNA, thereby leading to hypersensitivity of cancer cells to DNA-damaging chemotherapeutics. Taken together, our results uncover a plausible mechanism underlying the DDR sustaining and might represent an attractive therapeutic strategy in improvement of DNA damage-based anticancer therapies.
Ruyuan Yu, Yameng Hu, Shuxia Zhang, Xincheng Li, Miaoling Tang, Meisongzhu Yang, Xingui Wu, Ziwen Li, Xinyi Liao, Yingru Xu, Man Li, Suwen Chen, Wanying Qian, Li-Yun Gong, Libing Song, Jun Li

2754 related Products with: LncRNA CTBP1-DT-encoded microprotein DDUP sustains DNA damage response signalling to trigger dual DNA repair mechanisms.

10 100ug Lyophilized1mg100ug Lyophilized1mg100ug100ug Lyophilized50 100ul1g100ug

Related Pathways

paperclip

#35805102   2022/06/24 To Up

Aldehyde Dehydrogenase 1B1 Is Implicated in DNA Damage Response in Human Colorectal Adenocarcinoma.

Aldehyde dehydrogenase 1B1 (ALDH1B1) has been correlated with colorectal tumorigenesis and is considered a potential biomarker for colon cancer. Its expression has been associated with attenuation of the cell cycle in the G2/M phase and resistance to DNA damaging agents. The present study examines the role of ALDH1B1 in DNA damage response (DDR) in human colorectal adenocarcinoma. To this end, we utilized an isogenic HT29 cell line pair differing in the expression of ALDH1B1. The overexpression of ALDH1B1 was related to the translational upregulation of the total and phosphorylated (at ser15) p53. Comet and apoptosis assays revealed that the expression of ALDH1B1 protected HT29 cells from etoposide-induced DNA damage as well as apoptosis, and its overexpression led to increased constitutive phosphorylation of H2AX (at ser139). Furthermore, the expression profile of a variety of DNA damage signaling (DDS)-related genes was investigated by utilizing the RT profiler™ PCR array. Our results demonstrated that ALDH1B1 triggered a transcriptional activation of several DNA repair-related genes (, , and ). Finally, Spearman's rank correlation coefficient analysis in 531 publicly available colorectal adenocarcinoma clinical samples indicated the statistically significant positive correlation between ALDH1B1 and DDR and repair genes or proteins, such as APEX1, FEN1, MPG, UNG, XRCC1, DDB1, XPC, CIB1, MRE11, PRKDC, RAD50, RAD21, TP53BP1, XRCC6 and H2AX. Collectively, our results suggest that ALDH1B1 may play an essential role in the DDR and DNA repair processes. Further studies on ALDH1B1 will elucidate its precise role in DDR.
Ilias Tsochantaridis, Alexandros Kontopoulos, Georgia-Persephoni Voulgaridou, Margaritis Tsifintaris, Charisios Triantafyllou, Aglaia Pappa

1329 related Products with: Aldehyde Dehydrogenase 1B1 Is Implicated in DNA Damage Response in Human Colorectal Adenocarcinoma.

100 μg100ug Lyophilized 100 UG100 μg100ug Lyophilized100 ul 100ul100 μg100ug Lyophilized100 μg100 μg

Related Pathways

paperclip

#35736104   2022/06/10 To Up

Post-Translational Modifications of PCNA: Guiding for the Best DNA Damage Tolerance Choice.

The sliding clamp PCNA is a multifunctional homotrimer mainly linked to DNA replication. During this process, cells must ensure an accurate and complete genome replication when constantly challenged by the presence of DNA lesions. Post-translational modifications of PCNA play a crucial role in channeling DNA damage tolerance (DDT) and repair mechanisms to bypass unrepaired lesions and promote optimal fork replication restart. PCNA ubiquitination processes trigger the following two main DDT sub-pathways: Rad6/Rad18-dependent PCNA monoubiquitination and Ubc13-Mms2/Rad5-mediated PCNA polyubiquitination, promoting error-prone translation synthesis (TLS) or error-free template switch (TS) pathways, respectively. However, the fork protection mechanism leading to TS during fork reversal is still poorly understood. In contrast, PCNA sumoylation impedes the homologous recombination (HR)-mediated salvage recombination (SR) repair pathway. Focusing on budding yeast, we summarized PCNA related-DDT and repair mechanisms that coordinately sustain genome stability and cell survival. In addition, we compared PCNA sequences from various fungal pathogens, considering recent advances in structural features. Importantly, the identification of PCNA epitopes may lead to potential fungal targets for antifungal drug development.
Gemma Bellí, Neus Colomina, Laia Castells-Roca, Neus P Lorite

2522 related Products with: Post-Translational Modifications of PCNA: Guiding for the Best DNA Damage Tolerance Choice.

100.00 ul1mg 6 ml Ready-to-use 100ug 5 lt100 mg5L100ug150 ug500gm

Related Pathways