Periodic Reporting for period 4 - CFS modelling (Chromosomal Common Fragile Sites: Unravelling their biological functions and the basis of their instability)
Période du rapport: 2020-09-01 au 2022-07-31
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.
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.
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.