DNA REPAIR BY POL ? · Mechanisms of DNA repair by human DNA polymerase lambda
6РП — Действия „Мария Кюри“
- Период
- 2005-11-09 → 2007-11-08
- Финансиране от ЕС
- 80 000 €
- Участници
- 1
- Схема
- IRG
Линиите свързват координатора с партньорите. За проекти отпреди 2014 г. CORDIS не винаги дава точни координати. Тези точки са на ниво град или държава.
Накратко на български
ДНК полимеразата lambda помага за поправянето на уврежданията в ДНК, като например при двойно разкъсване на нишките. Разбирането на нейните генетични вариации помага да се обясни защо някои хора имат по-висок риск от мутации и развитие на рак на ректума.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - DNA REPAIR BY POL? (Mechanisms of DNA repair by human DNA polymerase lambda)
Human DNA polymerase lambda is a recently identified DNA repair polymerase whose biochemical properties are partly similar to those of Pol beta, suggesting a role of Pol beta in DNA repair. Indeed, as Pol beta, Pol lambda has an intrinsic dRP lyase, an activity that is critical for the BER pathway. Unlike Pol beta, Pol lambda contains an N-terminal BRCT domain, required for a stable interaction with non-homologous end-joining (NHEJ) factors, which suggests the involvement of Pol lambda in double-strand break (DSB) repair. Moreover, the interaction of Pol lambda with PCNA and its capacity to extend base-pairs containing different kinds of DNA lesions, suggest also a role in damage tolerance, collaborating in translesion synthesis. By comparing normal and tumoral samples, we identified and characterised a single nucleotide polymorphism (SNP) in human Pol lambda, resulting in amino acid change Arg to Trp in codon 438 (R438W). Interestingly, an elevated expression of this natural variant produces a significant increase in mutation frequency in vivo. In agreement with a causal effect, in vitro enzyme activity assays of both Arg and Trp 438 allelic variants showed a decrease in the fidelity of the W438 variant. Resolution of the 3D-structure of this natural variant of human Pol lambda allows discussing the molecular basis of this mutator W438 variant. Therefore, besides the more well-known loss-of-function mutations, polymorphic variants in DNA repair genes could substantially alter the overall DNA repair capacity, increasing the risk of mutations associated to repairing damaged DNA. Cancer-association studies of this Trp438 polymorphic variant were carried out, indicating a significant association of this natural mutator variant with rectal cancer.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
DNA polymerases are essential components of the molecular machinery that replicates and repairs DNA in the cell. Human DNA polymerase lambda (Pol lambda) is a newly discovered polymerase implicated in base excision repair and double-stranded break repair, two processes critically important in assuring genetic stability. Research described in this proposal aims at a structural and functional characterization of Pol lambda in human cells. The objective is to gain understanding about its mechanism of action by application of a range of biochemical and cell biology methodologies. A detailed analysis of the interaction of Pol lambda with proliferating cell nuclear antigen (PCNA) will be complemented with genome-wide search of other repair components that inte ract with Pol lambda. Purified proteins and synthetic DNA templates will be used in ‘ in vitro’ assays with the goal of defining the natural DNA substrates and the kinetic parameters of the repair reactions. The function of Pol lambd a will be further investigated by assaying a variety of cytotoxic agents in cell lines in which expression of Pol lambda can be artificially modulated. Special emphasis will be given to potential role of Pol lambda in tumour development. As part of the Marie Curie Action, the goal of this grant is support for the long-term reintegration of a highly experienced researcher in the European Research Area. The applicant has spent twelve years performing research in biochemistry in highly recognized institutions in the United States, and aims to transfer the gained expertise to a centre of excellence in the European Union. In this regard this proposal directly contributes to the European policy of return of European investigators from abroad, enhancement of th eir mobility, and the fostering of national and international collaborative links among researchers.
Оригинален текст от CORDIS (на английски).
Участници
- CENTRO DE BIOLOGIA MOLECULAR SEVERO OCHOA, CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS · MADRIDКоординаторНиво градИспания
Връзки
Данни: CORDIS, © Европейски съюз