Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability

Información del proyecto

CFS modelling

Identificador del acuerdo de subvención: 679068

DOI

10.3030/679068

Proyecto cerrado

Fecha de la firma de la CE 13 Enero 2016

Fecha de inicio 1 Mayo 2016

Fecha de finalización 31 Julio 2022

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 499 711,00

Aportación de la UE

€ 1 499 711,00

Coordinado por

AGENCIA ESTATAL CONSEJO SUPERIOR DE INVESTIGACIONES CIENTIFICAS
Spain

Periodic Reporting for period 4 - CFS modelling (Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability)

Período documentado: 2020-09-01 hasta 2022-07-31

Resumen del contexto y de los objetivos generales del proyecto

In this project, we aimed to characterize the physiological functions and the mechanisms that regulate chromosomal Common Fragile Sites (CFSs) stability. CFSs are unusual genomic regions conserved in all individuals that are prone to break especially under conditions of replication stress (RS). Critically, CFSs are hotspots for chromosomal translocations and rearrangements in cancer. In other words, CFS instability drives tumorigenesis. Therefore, the study of the regulation of CFSs may unmask novel therapeutic strategies for cancer treatment. In addition, we expect that the knowledge generated in this project will contribute to opening new directions in cancer research that may have an important impact in society.

We have generated the first proteomic characterization of CFS, showing that many DDR repair factors localize in these genomic regions. Besides, we have characterized the function of ATRX and SLX4IP regulating CFS stability.
On the other hand, we have generated a PICH-deficient mouse model with CFS instability that has allowed us to identify PICH as a potential therapeutic target for cancer treatment.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We have generated and characterized the first Pich KO mouse model (Albers et al, Cell Reports, 2018). PICH is a relevant protein involved in the resolution of ultra-fine anaphase bridges (UFBs) that derive from Common Fragile Sites (CFSs). We have found that PICH is essential for embryonic development due to the progressive accumulation of chromosomal instability. We have studied the influence of PICH on tumor initiation and progression. Particularly, we have used the lymphoma mouse model Emu-Myc in combination with Pich heterozygous and Pich conditional KO mice. Our results indicate that PICH deficiency delays the initiation and the progression of Myc-induced lymphoma (Castejón-Griñán et al., in preparation). Therefore, we believe that PICH is a promising therapeutic target for Myc-induced lymphomas and probably other cancer types.

On the other hand, we have successfully completed the first proteomics characterization of human CFSs. For that, we have implemented a FAND2-ChIP strategy coupled to Mass Spectrometry to identify dozens of proteins localizing at stressed CFSs. We have published this initial CFS-proteomics description, together with the characterization of one of the proteins identified -ATRX- at Nucleic Acid Research (Pladevall-Morera et al., Nuc Acid Res, 2019). We have found drugs that are toxic for ATRX deficient cancer cells (Pladevall-Morera D et al., Cancers, 2022), and we have characterized the relevance of SLX4IP maintaining CFS stability (Ingham et al, in preparation).

Finally, we have generated the first mouse model with a deletion of a whole CFS and we are finalizing our investigations related to the impact of FRA3B/FHIT loss in cancer and how FHIT deficiency can be exploited as a therapeutic opportunity.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

We have characterized the relevance of ATRX on CFS stability and we have characterized several novel factors involved in CFS stability, and which may have implications in cancer development.

On the other hand, we have generated a PICH KO mouse model and published its initial characterization during embryonic development (Albers et al, Cell Reports, 2018). PICH is a protein involved in the resolution of chromosomal ultra fine anaphase bridges (UFBs) that are formed at CFSs. Thus, PICH deficiency may lead to increased CFS fragility. We have observed that PICH KO cells indeed accumulate chromosomal instability and we are currently characterizing its connection to CFS instability. We believe that the PICH deficient model will be a very valuable tool to study CFS fragility in vivo. I believe that the characterization of PICH as a promising therapeutic target for Myc-induced lymphomas is a very relevant discovery (Albers et al, Cell Reports, 2018; Castejón-Griñán et al., in preparation). Indeed, we have initiated collaborations with the company Lead Discovery Center GmbH (Germany) to identify PICH inhibitors.

Graphical abstract of the project