Role of FANCD2 in the protection of chromosomal integrity during the cellular response to UV irradiation

FEDERICO MB; VALLERGA MB; RALD A; BOCCO JL; DIGIORGIO M; SORIA G; GOTTIFREDI V

Buenos Aires

Congreso; Congreso Argentino de Toxicología y I Jornadas de la Asociación Latinoamericana de Mutagénesis, Carcinogénesis y Teratogénesis Ambiental (ALAMCTA); 2015

Asociación Latinoamericana de Mutagénesis, Carcinogénesis y Teratogénesis Ambiental (ALAMCTA)

Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor in the FA pathway, is essential for the repair of replication-coupled DSBs generated at ICLs but not for the resolution of direct DSBs that arise independently from DNA replication. As a consequence, FANCD2 is accepted as a factor required for the resolution of collapsed forks arising from any type of stress. Notwithstanding, the participation of FANCD2 in the resolution of replication-coupled DSBs which are not derived from ICL-repair has not yet been reported. Intriguingly, FANCD2 is activated after UV irradiation but its biological relevance in this context is yet unclear. UV-irradiation generates only intra-strand crosslinks and therefore provides an optimal scenario for the study of FANCD2 functions beyond ICLs. Here we show that in opposition to ICLs, FANCD2 is dispensable for checkpoint activation, the accumulation of DNA-damage tolerance signals and cell survival after UV irradiation. Moreover, FANCD2 does not change the extent of the infrequent double strand breaks (DSBs) indirectly generated during the replication of UV-damaged DNA. Remarkably however, FANCD2 specifically protects such rare UV-triggered replication-coupled DSBs from aberrant processing, preventing the accumulation of micronuclei and non-homologous chromatidic exchanges. Hence, we unveil that while dispensable for short-term cell survival, FANCD2 is crucial to warrant chromosomal stability during UV-triggered replication stress