title: Chromosomal Integrity after UV Irradiation Requires FANCD2-Mediated Repair of Double Strand Breaks.
abstract: Fanconi Anemia (FA) is a rare autosomal recessive disorder characterized by hypersensitivity to inter-strand crosslinks (ICLs). FANCD2, a central factor of the FA pathway, is essential for the repair of double strand breaks (DSBs) generated during fork collapse at ICLs. While lesions different from ICLs can also trigger fork collapse, the contribution of FANCD2 to the resolution of replication-coupled DSBs generated independently from ICLs is unknown. Intriguingly, FANCD2 is readily activated after UV irradiation, a DNA-damaging agent that generates predominantly intra-strand crosslinks but not ICLs. Hence, UV irradiation is an ideal tool to explore the contribution of FANCD2 to the DNA damage response triggered by DNA lesions other than ICL repair. Here we show that, in contrast to ICL-causing agents, UV radiation compromises cell survival independently from FANCD2. In agreement, FANCD2 depletion does not increase the amount of DSBs generated during the replication of UV-damaged DNA and is dispensable for UV-induced checkpoint activation. Remarkably however, FANCD2 protects UV-dependent, replication-coupled DSBs from aberrant processing by non-homologous end joining, preventing the accumulation of micronuclei and chromatid aberrations including non-homologous chromatid exchanges. Hence, while dispensable for cell survival, FANCD2 selectively safeguards chromosomal stability after UV-triggered replication stress.
authors.affiliation: Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir, IIBBA/ CONICET, Buenos Aires, Argentina.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Federico
authors.affiliation: Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir, IIBBA/ CONICET, Buenos Aires, Argentina.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Vallerga
authors.affiliation: Laboratorio de Dosimetría Biológica, Autoridad Regulatoria Nuclear, Buenos Aires, Argentina.
authors.forename: Analía
authors.initials: A
authors.lastname: Radl
authors.affiliation: Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir, IIBBA/ CONICET, Buenos Aires, Argentina.
authors.forename: Natalia Soledad
authors.initials: NS
authors.lastname: Paviolo
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología/ CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Bocco
authors.affiliation: Laboratorio de Dosimetría Biológica, Autoridad Regulatoria Nuclear, Buenos Aires, Argentina.
authors.forename: Marina
authors.initials: M
authors.lastname: Di Giorgio
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología/ CONICET, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Gastón
authors.initials: G
authors.lastname: Soria
authors.affiliation: Cell Cycle and Genomic Stability Laboratory, Fundación Instituto Leloir, IIBBA/ CONICET, Buenos Aires, Argentina.
authors.forename: Vanesa
authors.initials: V
authors.lastname: Gottifredi
mesh_terms: D002842:Chromatids / Q000235:genetics / Q000528:radiation effects; D043171:Chromosomal Instability / Q000528:radiation effects; D002875:Chromosomes / Q000235:genetics / Q000528:radiation effects; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004249:DNA Damage / Q000528:radiation effects; D059766:DNA End-Joining Repair / Q000235:genetics / Q000528:radiation effects; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D004261:DNA Replication / Q000235:genetics* / Q000528:radiation effects; D005199:Fanconi Anemia / Q000235:genetics* / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics*; D042822:Genomic Instability / Q000235:genetics / Q000528:radiation effects; D006801:Humans; D034741:RNA, Small Interfering; D014466:Ultraviolet Rays
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D034741:RNA, Small Interfering