HEИндивидуална стипендия2024–2025

META-CYCLE · New players in the regulation of DNA replication fork speed

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

Период: 2024-01-01 → 2025-12-31
Финансиране от ЕС: 230 774 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Метаболизмът на раковите клетки в мозъка влияе върху скоростта, с която се копира ДНК. Разбирането на тези механизми помага за по-доброто познаване на развитието на туморите и търсенето на нови методи за лечение.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

New players in the regulation of DNA replication fork speed

Faithful DNA replication is essential for cell division and organismal health. When this process goes wrong, replication stress arises—a defining hallmark of cancer cells—leading to stalled replication forks, DNA damage accumulation, and genomic instability. Understanding the molecular mechanisms that govern how fast DNA is copied, and how this is coordinated with cell cycle progression, represents a critical frontier in cancer biology with direct therapeutic implications. The META-CYCLE project was designed to uncover the intricate connections between cellular metabolism, cell cycle regulation, and DNA replication fidelity. The central hypothesis was that metabolic rewiring in rapidly dividing cancer cells is not simply a passive supply chain for building blocks, but an active regulatory layer directly controlling replication fork speed and genomic stability. Primary objectives: • Identify metabolic signatures that predict dysregulated DNA synthesis in response to cell cycle alterations (WP1) • Characterise the molecular mechanisms by which metabolic enzymes regulate replication fork dynamics and genome stability through direct modulation of replisome components (WP2) • Discover new metabolic regulators of S-phase progression and DNA synthesis speed through systematic screening (WP3) The project focused on glioblastoma—one of the most aggressive and treatment-resistant brain cancers (~3–4 per 100,000 people annually; median survival <15 months)—while generating insights broadly applicable across cancer types.

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

Цел на проекта

Faithful eucaryotic cell division requires spatio-temporal orchestration of multiple sequential events. Among the crucial steps to providing the daughter cells with identical set of chromosomes is the DNA replication. During this phase, cells coordinate the speed of DNA synthesis with the length of the cell cycle to ensure genome integrity. To do so, growth factors and metabolic signals are integrated primarily by D-type Cyclins. Indeed. their deregulation can directly lead to some of the hallmarks of cancer by causing proliferation that is independent of normal extracellular cues. We previously demonstrated that aberrant accumulation of Cyclin D1 results in a faster cell cycle, with uncontrolled speed of DNA replication fork progression and genome instability (Maiani & Milletti et al., 2021). Despite, frequently altered in many tumors (Musgrove et al., 2011), a unifying theory that clarify how Cyclin D1 promote cancer transformation is still lacking. In the lab of Prof. Jiri Bartek, it was previously shown that PARP1 inhibition increases replication fork speed (Maya-Mendoza et al., 2018). PARP1i uncouples the leading and lagging DNA synthesis resulting in fast fork speed and genome instability. However, it is currently unknown whether the aberrant accumulation of Cyclin D1 has similar effect on DNA synthesis as PARPi. Furthermore, it is also undetermined whether aberrant levels of Cyclin D1 could trigger metabolic changes that accelerate the speed of DNA synthesis. Taking advantage of our previous observations, we aim with this proposal to: i) identify metabolic signatures that can predict dis-regulated DNA synthesis in response to cell cycle alterations; ii) define the molecular mechanism of how cyclin D1 accumulation induces accelerated fork speed; iii) identify new metabolic genes involved in the control of S phase progression and the speed of DNA synthesis by CRISPR-Cas9 screening technology; iv) suggest druggable targets that could be used in cancer therapy.

Оригинален текст от CORDIS (на английски).

Участници

KRAEFTENS BEKAEMPELSE · KoebenhavnКоординаторДания