THE CONTRIBUTION OF FANCD2 TO THE CELLULAR RESPONSE TO UV IRRADIATION

FEDERICO M, VALLERGA M, MANSILLA S, SPERONI J, HABIF M, RIERA M, GOTTIFREDI V

Foz do Iguazu

Conferencia; 11th International Conference on Environmental Mutagens; 2013

SBMTCA/ALAMCTA

Interstand crosslinks (ICLs) are very toxic lesions generated by agents such as mitomycin C (MMC). The removal of such lesions involves the activation of three mechanisms: Nucleotide Excision Repair (NER), Translesion DNA Synthesis (TLS) and Homologous Recombination (HR), which are spatially and temporally coordinated by the Fanconi Anemia (FA) pathway. In fact, mutations in FA genes steeply increase genomic instability and cell sensitivity to MMC. Similar effects where observed when using another drug, cisplatin, which causes multiple lesions including a limited fraction of ICLs accumulation. Intriguingly, the contribution of the FA pathway to the resolution of other type of lesions is currently unknown. Since FANCD2 ubiquitination, a key marker of the activation of the FA pathway, is upregulated after treatment with UV light, a damaging agents that does not induce ICLs accumulation, we thought this was a potentially interesting source of DNA damaging signals that would allow us to investigate the role of the FA pathway beyond ICLs. We have tested whether FANCD2 is required for the activation of major pathways activated after UV irradiation such as checkpoint signal and translesion DNA synthesis. We are also exploring the effect of FANCD2 in the accumulation of markers of replication-associated stress such as H2AX and 53BP1. We are also evaluating the effect of FANCD2 on cell viability and genomic stability after UV irradiation. This information might allow us to predict if FANCD2 contributes to the cellular response to DNA lesions other than ICLs, being this information very valuable when exploring alternative therapies for patient treatment.