H2020Индивидуална стипендия2019–2021

SinMolTermination · Single-molecule visualisation of eukaryotic DNA replication termination to uncover novel mechanisms of replication stress

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

Период: 2019-02-11 → 2021-04-15
Финансиране от ЕС: 183 455 €
Участници: 1
Схема: MSCA-IF-EF-RI

Линиите свързват координатора с партньорите.

Накратко на български

Процесът на завършване на репликацията на ДНК при еукариотите се наблюдава чрез визуализация на отделни молекули. Разбирането на тези механизми помага при разработването на нови терапии срещу рак и изучаването на причините за стареенето и неврологичните заболявания.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Single-molecule visualisation of eukaryotic DNA replication termination to uncover novel mechanisms of replication stress

Perturbation to the replication of the human genome, so called replication stress, is a key endogenous source of genome instability that leads to ageing, neuropathology and cancer development. DNA replication occurs in three stages: initiation, elongation and termination. Fundamental knowledge about replication initiation and elongation led to the development of replication-stress inducing drugs that target rapidly dividing cancer cells. However, despite recent breakthroughs there is still little understanding about the molecular mechanism of termination and how it can generate replication stress. This is due to the recalcitrant nature of termination to traditional experimental approaches. We seek to fill this significant gap in knowledge within the eukaryotic DNA replication field by developing novel technology and approaches to study DNA replication termination. Our multidisciplinary approach will permit direct and continuous visualization of individual eukaryotic replication forks during replication elongation and termination. Our results are anticipated to provide a significant and unique breakthrough in the replication field, spearhead new avenues of cancer therapy development, as well as providing novel assays and research tools for the international research community. We were successful in the creation of a single-molecule imaging approach to study replication termination but ultimately further progress and dissemination of results was prevented due to the Covid-19 pandemic.

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

Цел на проекта

Replication-stress is a key driving force of cancer development, neurodegeneration and ageing. Many sources of replication stress associated with the initiation and elongation phases of DNA replication have been discovered. In contrast, little is known about the mechanisms of replication termination and termination-associated replication stress. Recent breakthroughs identified the first elements of a mechanism of replication termination that involved ubiquitination of the Mcm7 subunit of the CMG helicase. However, we do not know how terminating replisomes signal themselves for ubiquitination, nor how this is regulated both temporally and spatially along chromatin. By combining sophisticated single-molecule imaging techniques with the ability of Xenopus extracts to replicate DNA in a physiological manner, we will for the first time, be able to watch individual replication forks terminate. Importantly, our multidisciplinary and single-molecule approach will allow us to bypass the constraints posed by ensemble techniques that have hindered progress in this field. Specifically, we will define the spatial and temporal conditions upon which Mcm7 becomes ubiquitinated and how this is connected to the fate of the CMG helicase during termination. These observations will enable us to determine a complete mechanistic understanding of vertebrate replication termination for the first time. We will also discover how failed DNA replication termination triggers replication stress. Revealing these novel mechanisms of replication stress allows for new therapeutic targets to be identified and potentially facilitates new disease prevention strategies to be recognised.

Оригинален текст от CORDIS (на английски).

Участници

THE UNIVERSITY OF BIRMINGHAM · BirminghamКоординаторОбединеното кралство