Innovating Works

CLOCK

Financiado
Mechanisms of proliferation-independent mutation
DNA damage contributes to the ageing of tissues and causes mutations that drive cancer. However, the molecular mechanisms underlying many mutational processes are not understood, and neither is how much they contribute to disease.... DNA damage contributes to the ageing of tissues and causes mutations that drive cancer. However, the molecular mechanisms underlying many mutational processes are not understood, and neither is how much they contribute to disease. With a powerful new technology, I propose to close these major gaps for common ?clock? mutations of unknown origin. The recent genome sequencing revolution has revealed unexpected diversity in mutational patterns. One pattern in particular is intriguing as it behaves as a molecular ?clock?: the number of mutations increases over time and correlates with age. Although the textbook view of mutagenesis is that cell division is required to convert DNA damage into point mutations, surprisingly, non-dividing cells like neurons also accumulate ?clock? mutations as a function of time, indicating that ?clock? mutations arise without genome replication. Understanding how cells mutate independently of proliferation?and thus challenging the current paradigm of mutagenesis?is a fundamental question that has been hindered because assays to measure mutation require cell division. Excitingly, I have overcome this major obstacle by establishing a powerful strategy to sensitively detect mutations in single cells, genome-wide. My group will combine this approach with targeted genetic manipulations in cells and mice to answer two central questions. (1) How do cells mutate independently of proliferation? (2) What drives these mutations in tissues? My novel insights into endogenous DNA damage from mouse genetics and genomics, combined with the innovative sequencing strategy that I have established, uniquely position me to answer these long-standing questions. Together, the work proposed here will reveal the molecular mechanism(s) underlying the most common mutational process in humans: ?clock? mutation. The methods, data, and insights from these groundbreaking studies will directly impact cancer research and uncover novel sources of DNA damage during aging ver más
30/04/2027
KNAW
2M€
Perfil tecnológico estimado
Duración del proyecto: 61 meses Fecha Inicio: 2022-03-08
Fecha Fin: 2027-04-30

Línea de financiación: concedida

El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-03-08
Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:
ERC-2021-STG: ERC STARTING GRANTS
Cerrada hace 3 años
Presupuesto El presupuesto total del proyecto asciende a 2M€
Líder del proyecto
KONINKLIJKE NEDERLANDSE AKADEMIE VAN WETENSCH... No se ha especificado una descripción o un objeto social para esta compañía.
Perfil tecnológico TRL 4-5