Abstract PR05: Distinct BRCA1- and BRCA2-specific functions at stalled replication forks: Clinical implications for differences between BRCA1 and BRCA2 mutation-driven cancer
Notice bibliographique
Résumé
Abstract BRCA1 and BRCA2 are tumor suppressor genes, and germ line mutations in these two genes increase the risk of breast cancer. Both BRCA1 and BRCA2 are required for stabilization and repair of stalled replication forks. Stalled forks, when not resolved, lead to mutations, or collapse into double strand breaks (DSBs). Both outcomes result in what is commonly referred to as replication stress (RS), which, when chronic, is a driving force behind cancer development. However, it is not clear what are the differences, if any, between BRCA1 and BRCA2 dependent stabilization and repair of stalled replication fork. Getting a better understanding of how these two proteins help suppress RS will not only help reveal how they contribute to breast cancer suppression, but will also give us an insight into the differences in the spectrum of cancers in BRCA1 and BRCA2 mutation carriers. Such knowledge is also critical in designing better therapeutic options for BRCA1 and BRCA2 specific mutation carriers. Here we report a novel role for BRCA2 in suppressing RS by regulating RPA (replication protein A) accumulation on ssDNA (single stranded DNA) at stalled forks. More specifically, we show that BRCA2 is required for efficient turnover of RPA, and in absence of BRCA2 there is “persistent” accumulation of mostly un-phosphorylated RPA (at S33, T21 and S4/S8) at stalled forks. Furthermore, inefficient turnover of RPA in absence of BRCA2 not only results in fork collapse, as marked by increased accumulation of both 53BP1 and Mre11 at the site of stalling, but also leads to suppression of nucleotide excision repair (NER). No such persistent RPA coated ssDNA is observed in BRCA1 depleted cells, suggesting that this intermediate is exclusive to BRCA2 deficiency. We also show that generation of this intermediate was not dependent on Mre11 implying that accumulation of RPA coated ssDNA was not a result of excessive DNA processing by Mre11 exonuclease in absence of BRCA2. To determine whether stalled fork repair (SFR) is defective in normal/healthy breast cells from BRCA2 mutation carriers (BRCA1mut/+), we generated 12 primary mammary epithelial cell (MECs) strains from prophylactic mastectomies performed on BRCA2 mutation carrying women. BRCA2+/+ control MECs were derived from tissue collected during reduction mammoplasties. Our current data shows that BRCA2mut/+ strains are defective in SFR. Importantly, we also show that BRCA2mut/+ strains, and not BRCA1mut/+ strains, are haploinsufficient for NER. Inefficient NER in BRCA2mut/+ strains, and not in BRCA1mut/+ strains, suggests an increased risk in BRCA2 mutation carriers for accumulating DNA lesions that require NER for repair. Such a defect is known to contribute towards increased risk for melanoma, and could partly explain why women with BRCA2 mutation, and not BRCA1 mutation, are prone to increased risk for skin lesions including melanoma. This mechanistic difference between BRCA1 and BRCA2 response at stalled replication forks, and subsequently a crosstalk with NER pathway, might also contribute towards other clinical differences observed in BRCA1 and BRCA2 mutation driven breast cancer. This abstract is also being presented as Poster A35. Citation Format: Haohui Duan, Rachel Reed, Judy Garber, Shailja Pathania. Distinct BRCA1- and BRCA2-specific functions at stalled replication forks: Clinical implications for differences between BRCA1 and BRCA2 mutation-driven cancer [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 PR05.
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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 | 0,001 | 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 ».