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Molecular and structural mechanisms for metazoan replication origin specificatio...

Molecular and structural mechanisms for metazoan replication origin specification Cellular life depends on the timely and accurate duplication of chromosomal DNA through semi-conservative replication to sustain genomic integrity and organismal viability. In all domains of life, DNA replication relies on dedicat... ver más

30/06/2023

FMI

2M€

Presupuesto del proyecto: 2M€

Líder del proyecto

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL R... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

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Financiación concedida El organismo H2020 notifico la concesión del proyecto el día 2023-06-30

ERC-2017-STG: ERC Starting Grant

I+D

Cerrada hace 8 años

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2 Participantes

FMI

1.50M€ | Lider

RESILUX IBERICA PACKAGING

375.06K€ | Participante

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Duración del proyecto: 69 meses Fecha Inicio: 2017-09-11
Fecha Fin: 2023-06-30

Líder del proyecto

FRIEDRICH MIESCHER INSTITUTE FOR BIOMEDICAL R... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Presupuesto del proyecto 2M€

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto Cellular life depends on the timely and accurate duplication of chromosomal DNA through semi-conservative replication to sustain genomic integrity and organismal viability. In all domains of life, DNA replication relies on dedicated initiator proteins that recognize and bind specific genomic sites, termed replication origins, to facilitate the loading of ring-shaped replicative helicases onto DNA. While origin recognition by initiators is determined by specific DNA sequences in prokaryotes and in the eukaryote S. cerevisiae, origin specification in higher eukaryotes instead appears to rely on chromatin context and DNA structure. Yet, how initiators help specify replication origins at the molecular level and how their binding sites are established in higher eukaryotes remain foremost and long-standing questions in the field. This research proposal focuses on uncovering the molecular and structural principles for chromosomal binding site selection by the eukaryotic initiator, the origin recognition complex (ORC), in metazoan systems. Employing integrated biochemical, structural, and cell-based approaches, we aim to 1) elucidate how ORC binds DNA and how DNA structural elements contribute to this interaction, 2) determine how nucleosomes are recognized by ORC, and 3) identify auxiliary binding partners of ORC and establish how they contribute to origin specification. The outcomes of our proposed efforts will have far-reaching implications for multiple scientific fields by defining mechanistic links between chromatin architecture and DNA replication initiation, and they will set the foundation to understand at the molecular level how the replication initiation program is altered during cell differentiation and development. Our studies also have significant biomedical relevance, as failure to precisely replicate chromosomal DNA leads to genetic instability, which in turn underpins many human diseases, including cancer and certain developmental disorders.

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