The Impact of Telomere Shortening in Dyskeratosis Congenita Cells on DNA Damage Response Pathways.
Notice bibliographique
Résumé
Abstract Dyskeratosis congenita (DC) is an inherited multisystem disorder of premature aging, typically characterized by bone marrow failure, mucosal leukoplakia, abnormal skin pigmentation, and nail dystrophy. The X-linked and autosomal dominant forms of DC are associated with mutations in genes that affect telomerase activity resulting in a decrease in telomere length. DC, like other bone marrow failure disorders, is associated with ineffective hematopoiesis and a cancer predisposition. Standard treatment of bone marrow failure or cancer requires cytotoxic therapy, and clinical observations suggest DC patients have an increased sensitivity to cytotoxic therapy. To explain this, we hypothesized that the short telomeres in somatic cells from DC patients could alter the activity and/or expression of several proteins involved in DNA repair or the response to cellular stress including p16, p53 and p21. Lymphocytes from five DC subjects and age-matched controls were stimulated to grow in vitro in the presence of various cytotoxic agents with different modes of action, including Taxol (antimitotic agent and microtubule inhibitor) and Etoposide (topoisomerase inhibitor and DNA damaging agent). In addition, we tested fibroblasts and keratinocyte extracted from skin biopsies from DC and control subjects that were serially passaged. Cellular proliferation and cell death were monitored by cell counts and flow cytometry. Western blotting was used to measure steady state and DNA damage- induced expression of tumor suppressor protein p53 and other proteins involved in DNA damage response signaling pathway, including p16 and p21 in relation to telomere length. Results of flow cytometry accompanied by direct visualization showed a decreased proliferation of DC lymphocytes compared to normal cells, and this growth disadvantage was further accentuated following cell exposure to cytotoxic agents. DC lymphocytes exposed to 10−6 M Taxol showed a decrease in cellular proliferation between 3 and 8 fold while normal control cells exposed to the same agents exhibited only a 3 to 4 fold decrease in cell growth. Similarly DC lymphocytes exposed to Etoposide were inhibited to a greater extent than control cells. Western blot analysis of whole cell lysates indicated a difference in DNA damage response proteins. Of note, lymphocytes from several DC subjects exposed to Taxol did not upregulate p53 expression, while inducible levels were noted in Taxol-treated control cells. In contrast, DC and control lymphocytes exposed to Etoposide upregulated p53 in a similar dose dependent manner. No differences were noted in DC versus control lymphocytes with regards to basal or chemotherapy induced p16 expression. Interestingly, late passage DC fibroblasts displayed enhanced basal expression of p16. These results support the clinical observation of increased “chemosensitivity” in DC subjects and suggest that diminished telomerase activity and premature telomere shortening may interfere with normal DNA damage and stress response pathways. These data are also consistent with our finding that DC fibroblasts, keratinocytes, and lymphocytes have a reduced cell proliferative lifespan. Further studies are needed to dissect the role of telomeres in the cellular response to various types of DNA damage.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 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) | 0,002 | 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 source (Gemma direct ou Codex distillé), 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 ».