Abstract IA20: Phosphorylation of BRCA1 by CHK2 mediates resection activity and recruitment of BRCA2
Notice bibliographique
Résumé
Abstract There is genetic evidence that Chk2, BRCA1 and BRCA2 are functioning in the same pathway of DNA repair, but the links between the proteins are poorly understood. We have previously shown that BRCA1's regulation of homologous recombination (HR) is dependent on Chk2-mediated phosphorylation of BRCA1 at serine 988 (BRCA1-S988). We also found that BRCA1 regulates BRCA2 recruitment in response to DNA damage, which is also dependent on the phosphorylation of BRCA1 at Serine-988. Furthermore, in HCT116/Chk2-/- cells and in MCF7 cells with depleted Chk2, the same effects on HR and BRCA2 recruitment has been found as found in cells expressing the BRCA1-S988A protein. However, in both cases, BRCA1 is recruited to chromatin and into nuclear foci, so the effect of Chk2 is not affecting the recruitment of BRCA1. BRCA1-S988A shows a defect in RPA phosphorylation in response to replication stress and DNA damage. After global DNA damage with X-rays, MRE11 foci form at double-strand breaks, and in S and G2 phases of the cell cycle, an association with CTIP is observed transiently. In the presence of BRCA1-S988A, MRE11 co-localized with CTIP persists for much longer, and results in reduced single-stranded DNA bound by RPA. In response to a site-specific DSB induced by I-SceI nuclease, BRCA1-S988A can localize to the vicinity of the break, but not directly at the broken end, as observed by chromatin immuno-precipitation. A physical assay of resection, which distinguishes single-stranded DNA from double-stranded DNA by its susceptibility to restriction enzyme digestion, shows that BRCA1-S988A expressing cells have an initiation of resection, but a failure to extend resection up to 2 kb observed in wild-type cells. The recruitment of Exo1 is being investigated. Therefore, these results demonstrate that BRCA1-S988 plays key role in regulating the extent of resection, which in turn impedes the recruitment of BRCA2 to sites of resected DSB. Chk2 inhibition may exacerbate the defect in HR, particularly in cells with a partial or mild HR-deficiency, which is found quite commonly in human tumor cells, suggesting that combination of Chk2 and PARP inhibitors may be a useful combination DNA repair based therapy. Citation Format: Simon N. Powell. Phosphorylation of BRCA1 by CHK2 mediates resection activity and recruitment of BRCA2 [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 IA20.
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 | 0,000 | 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 ».