Abstract A06: Regulation of homologous recombination by the SUMO ligase NSMCE2
Notice bibliographique
Résumé
Abstract Introduction: The purpose of this study is to determine the role of the E3 SUMO ligase NSMCE2 in BLM regulation and homologous recombination (HR). Background: DNA damage generated during replication is a major source of mutations and failure to repair this damage can cause genomic instability. HR is a high-fidelity DNA repair pathway activated primarily by replication-associated DNA damage. Numerous HR proteins are regulated by sumoylation, but the mechanisms that control sumoylation and their roles in HR are poorly understood. Cells deficient in the SUMO E3 ligase NSMCE2 are sensitive to DNA damaging agents and have defects in HR. Our preliminary data indicated that BLM sumoylation is dependent on NSMCE2. Because BLM sumolyation is required to recruit RAD51 to stalled forks, we hypothesized that NSMCE2-deficient cells are deficient in HR due to a defect in BLM-dependent RAD51 recruitment. Results: To test this hypothesis, we transfected HeLa cells with siRNAs specific to NSMCE2 and tested whether cells could recruit RAD51 to replication forks stalled with hydroxyurea (HU). Contrary to our hypothesis, we found that the amount of RAD51 protein that accumulated at stalled forks was greater in HU-treated NSMCE2-deficient cells compared to HU-treated control cells. To our surprise, the amount of single-stranded DNA binding protein RPA was diminished by half in HU-treated NSMCE2-deficient cells and DNA damage signaling was similarly diminished as evidenced by the lower levels of γ-H2AX. Consistent with the low levels of γ-H2AX, the double-strand breaks (DSB) that normally form after extended treatment with HU were also greatly diminished in NSMCE2-deficient cells. Consistent with previous reports, we found that the levels of HU-induced sister chromatid exchange were also low. These data indicated that despite the over-accumulation of RAD51 to sites of stalled replication forks, cells are unable to perform HR repair efficiently, indicating that RAD51 is unable to complete its function there. Conclusions: The hyper-accumulation of RAD51 at stalled forks we observed in NSMCE2-deficient cells suggests the sumoylation of one or more substrates by NSMCE2 is required for the remodeling of stalled forks that normally leads to unloading of RAD51 at the fork, strand breakage, and repair by HR. We suggest that the RAD51 accumulation that is observed in a substantial fraction of cancers may not be sufficient to demonstrate that the cells are HR proficient. Based on our data, RPA staining combined with RAD51 may be able to distinguish HR-proficient and deficient cells. Citation Format: Kelvin W. Pond, Christelle DeRenty, Mary Yagle, Nathan Ellis. Regulation of homologous recombination by the SUMO ligase NSMCE2 [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr A06.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».