Chromosomal Integrity after UV Irradiation requires FANCD2-mediated Repair of Double Strand Breaks.

MB FEDERICO, MB VALLERGA, A RALD, NP PAVIOLO, JL BOCCO, M DI GIORGIO, G SORIA, GOTTIFREDI V.

PLOS GENETICS

PUBLIC LIBRARY SCIENCE

Lugar: San Francisco; Año: 2016

1553-7390

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 FANCD2 is dispensable for checkpoint activation after UV irradiation. Moreover, in opposition to ICLs, the accumulation of DNA-damage tolerance signals and cell survival after UV irradiation is not affected by FANCD2 depletion. Moreover, FANCD2 depletion 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 warrants chromosomal stability during UV-triggered replication stress.