HEИндивидуална стипендия2024–2026

hnRNPs-DNA damage · Dissecting the molecular mechanisms underlying hnRNP exclusion from DNA double-strand breaks.

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

Период: 2024-04-01 → 2026-03-31
Финансиране от ЕС: 173 847 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Белтъците hnRNP се извеждат от местата, където ДНК е прекъсната, за да се освободи място за поправка. Разбирането на този механизъм помага да се разбере как клетките поддържат стабилността на генома и осигуряват точно възстановяване на уврежданията.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Dissecting the molecular mechanisms underlying hnRNP exclusion from DNA double-strand breaks.

DNA double-strand breaks (DSBs) are highly toxic lesions that must be efficiently repaired to maintain genome stability. Cells react to DSBs by activating a complex signalling network termed the DSB response which senses, signals and repairs DSBs. Emerging organizers of this pathway are various RNAs and RNA-binding proteins (RBPs). Yet, our knowledge on how these RNAs and RBPs participate in the DSB response and how they are regulated is largely incomplete. Our laboratory developed a targeted microscopy screen to investigate the mobility of a RBP family called heterogeneous nuclear ribonucleoproteins (hnRNPs) at DSB sites. Work from our lab and other labs have shown that many hnRNPs are actively excluded from damaged chromatin soon after the induction of DSBs. However, the mechanism and significance of this exclusion are still unexplored. This project fills this important gap by providing a detailed knowledge of how hnRNPs are integrated into the DSB response. Using cutting-edge imaging technologies, we propose to characterize the exclusion properties of hnRNPs at DSBs and to understand the significance of hnRNP exclusion for DNA repair (Aim 1). We also aim to identify the local protein and RNA complexes associated with hnRNPs at DSB sites using proximity labelling proteomics and RNA-sequencing approaches (Aim 2). Overall, our results show that the exclusion of hnRNPs to DSBs participates in the coordination between RNA biology and the DSB response and is essential to facilitate a timely and accurate DSB repair.

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

Цел на проекта

DNA double-strand breaks (DSBs) are toxic lesions that must be efficiently repaired to maintain genome integrity. Following DNA damage, cells activate a multi-layered signalling and repair network termed the DSB response. Emerging organizers of this DSB response are various RNAs and RNA-binding proteins, which display characteristic localization dynamics at the damaged-chromatin. The laboratory of Stephanie Panier recently showed that many heterogeneous nuclear ribonucleoproteins (hnRNPs) are actively excluded from damaged chromatin soon after the induction of DSBs. The exact purposes of hnRNP exclusion and the underlying regulatory mechanisms remain to be determined. In my postdoctoral project, I propose to study why and how hnRNPs are excluded from damaged chromatin. To this end, 1) I will characterize the exclusion properties of the hnRNPs at DSBs using cellular models and unique genetic and microscopy approaches. 2) I will also identify protein and RNA complexes associated with hnRNPs at DSB sites using proximity labelling proteomics and RNA-sequencing approaches. In studying these hnRNPs, I will unravel the new mechanisms by which RNAs help to organize the DSB response. The combination of state-of-the-art cell biological and omic approaches will enable me to go well beyond the current knowledge of the field to characterize novel factors and mechanisms that coordinate RNA biology at DSB sites. Since genome instability and defects in RNA metabolism are both directly linked to the pathogenesis of cancer and also neurodegeneration, my findings will have direct implications for human health.

Оригинален текст от CORDIS (на английски).

Участници

MAX-PLANCK-GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN EV · MUNCHENКоординаторГермания