H2020Индивидуална стипендия2016–2019

RAGES · Molecular determination of Rif1-Associated Genomic Elements and their function in regulating genome activity and integrity

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2016-03-31 → 2019-03-31
Финансиране от ЕС: 195 455 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Протеинът Rif1 регулира начина, по който клетката поправя счупванията в ДНК нишките. Разбирането на този механизъм помага да се обясни появата на рак и първични имунни дефицити при болентите.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Molecular determination of Rif1-Associated Genomic Elements and their function in regulating genome activity and integrity

DNA double-strand breaks (DSBs) are highly toxic and must usually be accurately repaired to prevent oncogenic mutations. However, DSBs also represent necessary intermediates of recombination events required to create genetic diversity in immune repertoires and the germline. These distinct cellular contexts require that DSBs are differentially metabolised to achieve the required genetic outcome. Thus a complex system has evolved to regulate DSB repair. Rif1 is a critical regulator of DSB repair, whose recruitment to chromatin at DSBs by the 53BP1 chromatin reader plays a critical role in protecting the integrity of DNA ends during DSB break repair by the non-homologous end joining pathway. However, little is known about how 53BP1-RIF1 protein complexes regulate chromatin structure at DNA damage sites, and how this impacts on the molecular mechanisms that underpin DNA repair. This proposal aimed to discover the mechanism in which Rif1 regulates DSB repair. Understanding the molecular function of the RIF1 protein is paramount, as mis-regulation of DSB repair at the level of Rif1/53BP1-deficiency manifests in primary immunodeficiency in mammals. Conversely, an inability to counteract Rif1/53BP1- dependent activities during DNA repair is associated with genomic instability that drives carcinogenesis. Interestingly, evidence suggests that Rif1 may also mediate gene-repression, raising the possibility that common Rif1-dependent mechanisms may regulate gene transcription and DNA repair. In examining: (1) the chromosomal contexts in which Rif1 operates; (2) the factors with which Rif1 cooperates; and (3) the phenotypic consequences of Rif1 loss; this proposal set out to test the overarching hypothesis that a common activity exerted by the Rif1 protein in chromatin plays a vital role in regulating both gene silencing and DNA repair activities. Thus successful completion of this project aims to discover vital, yet hitherto undefined mechanism that may link genome activity and stability.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

DNA double-strand breaks (DSBs) are highly toxic and must usually be accurately repaired to prevent oncogenic mutations. However, DSBs also represent necessary intermediates of recombination events required to create genetic diversity in immune repertoires and the germline. These distinct cellular contexts require that DSBs are differentially metabolised to achieve the required genetic outcome. Thus a complex system has evolved to regulate DSB repair. Rif1 was recently identified as a critical regulator of DSB repair, recruited to chromatin at DSBs by the 53BP1 chromatin reader. However, little is known about how these proteins cooperate to alter the chromatin landscape at DNA damage sites, and how this influences DNA repair decisions. Understanding the molecular basis of these proteins function is paramount, as misregulation at the level of Rif1/53BP1 is known to drive disease: loss of either protein results in primary immunodeficiency, while an inability to counteract Rif1/53BP1-dependent activities during DNA repair is associated with genomic instability that drives carcinogenesis. Interestingly, recent evidence suggests that Rif1 may also mediate gene-repression in certain chromatin contexts. This raises the possibility that the manner by which Rif1 regulates transcriptional control may be similar to its role in DNA repair. In this proposal, I seek to test my hypothesis that Rif1 mediates repressive chromatin states to regulate both transcription and DNA repair outcomes. My preliminary work and an array of unique cell lines and molecular reagents developed by my host laboratory, provide me with a unique and timely opportunity to examine this fascinating protein, and develop a better understanding of potentially common regulatory mechanisms that govern transcription and DNA repair.

Оригинален текст от CORDIS (на английски).

Участници

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordКоординаторОбединеното кралство