H2020Индивидуална стипендия2022–2024

DSB Architect · The role of chromosome conformation in DNA double-strand break repair

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

Период: 2022-09-01 → 2024-08-31
Финансиране от ЕС: 174 167 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Тритеизмерната организация на сестринските хроматиди и ролята на кохезинните комплекси определят как се поправят двойните счупвания в ДНК чрез хомологична рекомбинация. Разбирането на този процес помага да се разбере как клетката поддържа здравето си чрез точно възстановяване на генетичния материал.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

The role of chromosome conformation in DNA double-strand break repair

Eukaryotic cells often face damage to their DNA, including double-strand breaks (DSBs), which need proper repair to maintain the cell’s health. One highly accurate repair process is called homologous recombination. This error-free process uses an undamaged homologous DNA region as a template to repair the break. Given the vast size of human genomes, a random search for these matching regions would be highly inefficient. Indeed, homologous recombination is slower and less efficient when homologous DNA regions are on different chromosomes. However, after DNA replication, thanks the presence of an exact copy of each chromosome, homologous recombination becomes more efficient between the copies, called sister chromatids, due to their specific organization. Cohesin complexes play a crucial role in this organization, thus supporting more effective DNA repair. Cohesin complexes play two key roles in organizing sister chromatids: they create stable connections between them and form dynamic DNA loops within each chromatid. These loops shape specific domains that influence various processes in the nucleus, including DNA repair. The stable links formed by cohesin are crucial for efficient homologous recombination, as they help locate matching DNA sequences and restructure the repair sites. However, the exact function of this three-dimensional DNA organization in the repair process has remained unclear until now. The goal of this project was to understand how the three-dimensional organization of sister chromatids contributed to homologous recombination repair. Specifically, it aimed to 1) explore how the structure of sister chromatids affected and was affected by the repair process, and 2) identify key molecular factors that regulated chromosome conformation for efficient DNA repair. By combining microscopy- and sequencing-based assays, together with a novel sister chromatid sensitive Hi-C assay developed in the hosting lab, the Fellow has identified a role for sister chromatid organization, regulated by both cohesive and loop-extruding cohesin, in controlling the range and dimensionality of the homology search step during homologous recombination in human cells.

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

Цел на проекта

The integrity of eukaryotic genomes is constantly challenged by various endogenous and exogenous insults, whereby DNA double-strand breaks (DSBs) are particularly problematic. DSBs can be repaired by multiple pathways, but only the homologous recombination (HR) pathway ensures error-free repair. HR restores missing information around the lesion based on topological interactions with a homologous region on a distinct DNA molecule. HR-directed repair can function across homologous chromosomes in diploid organisms, but is much more efficient between sister chromatids in replicated chromosomes, indicating an important role of chromosome conformation in repair. Sister chromatids are organized by a dynamic interplay between cohesin-mediated loop extrusion, cohesin-mediated sister linkage, and chromatin-based affinity interactions. How these activities shape sister chromatids to support DNA repair is unclear. The proposed project aims to reveal how sister chromatid conformation governs DSB repair efficiency and pathway choice in human cells and to identify and characterize the key molecular factors regulating chromosome conformation for efficient DSB repair. Understanding how intra- and inter-molecular topological interactions contribute to DNA repair will become possible by using a new chromosome conformation capture technology developed in the hosting lab (sister-chromatid sensitive Hi-C). This technology will be combined with a system for acute DSB induction, automated imaging and genomic profiling of DNA repair factors, and targeted protein degradation of cohesin and its regulators to elucidate topological interactions underlying DSB repair. The proposed project will provide insights into how the core machinery shaping the three-dimensional organization of chromosomes contributes to the maintenance of genome integrity.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT FUER MOLEKULARE BIOTECHNOLOGIE GMBH · WienКоординаторАвстрия