CCAR2: at the crossroad between DNA repair, cell metabolism and stress signalling (CCReMeSS)

Description

All cells in the human body have the potential to become cancerous throughout the sequential acquisition of mutations. Mutations would appear as a byproduct of erroneous or uncomplete DNA repair. Strikingly, due to the high efficiency of DNA repair mechanisms, human
cells will rarely accumulate enough of those sequence alterations to became cancerous, and therefore an increased genomic instability is a hallmark of cancer. So, mutations in DNA repair pathways, and especially the repair of DNA breaks, are early on favored in many malignancies. On the other hand, radiotherapies and several chemotherapies are based in the high cytotoxicity of DNA breaks induced artificially by radiation or chemicals, respectively. This double role of DSBs repair in both, the genesis and treatment of cancer makes the study of DNA repair of great interest in cancer research.
Among many different factors involved in the repair of DNA breaks, thanks to the work developed in previous Plan Estatal Projects from our lab, we uncovered a protein named Cell Cycle and Apoptosis Regulator 2 (CCAR2). It is a multifunctional protein that acts as a melting point in which multiple and very different cellular pathways converge to elicit very varied responses that affect cellular fitness and homeostasis. CCAR2 affects many different cellular aspects that include cell cycle, mitotic progression, apoptosis, metabolism sensing, RNA splicing, chromatin and protein acetylation, transcriptional regulation, the circadian cycle, the DNA damage response, homologous recombination, cellular senescence, inflammation, etc. So, it is thought that CCAR2 acts as a hub that receives many different signals from those very different aspects of the cellular environment and can compute them, therefore reading the cellular context, and elicit a response that will resonate in many different cellular outcomes, allowing the cell to subtly finetune its fitness.
We are interested in this protein due to a plethora of preliminary results that put CCAR2 in the center of several regulatory networks controlling the repair of DNA breaks. Briefly, we have found that CCAR2 connects recombination regulation with the circadian cycle, dampening this repair pathway at nightfall and affecting the response to radiation; it is required for regulating resection and recombination in early but not late S-phase; and it is essential to mediate the Radioadaptative Response, a defensive mechanism that is activated when cells are exposed to low doses of radiation that protects temporarily those cells (and neighbor cells too) from larger radiation doses.
Overall, we aim to further our knowledge on how CCAR2. Our main hypothesis is that the CCAR2 is a key element in the molecular mechanism that ensures proper balance between DNA double strand breaks repair pathways and connects this with general cellular homeostasis in physiological conditions with an impact in pathology when deregulated. Based on that idea, we propose that understanding how CCAR2 is regulated and exert its function will help us to envision how cancer progress and open research avenues that might improve cancer treatments. In brief, we plan to uncover additional factors and post translational modification of this protein involved in modulating DNA break repair. We also want to deepen our understanding in how CCAR2 connects DNA repair with the cellular
metabolism and the stress response.

Project investigators

• Pablo Huertas Sánchez – Principal Investigator
• Maikel Castellano Pozo
• María Rosario Prados Carvajal

Funding entities

Agencia Estatal de Investigación

Ministerio de Ciencia, Innovación y Universidades

FEDER