A new role for Drosophila Aurora-A in maintaining chromosome integrity
Aurora-A is a conserved mitotic kinase overexpressed in many types of cancer. Growing evidence shows that Aurora-A plays a crucial role in DNA damage response (DDR) although this aspect has been less characterized. We isolated a new aur-A mutation, named aur-A949, in Drosophila, and we showed that it causes chromosome aberrations (CABs). In addition, aur-A949 mutants were sensitive to X-ray treatment and showed impaired γ-H2Av foci dissolution kinetics. To identify the pathway in which Aur-A works, we conducted an epistasis analysis by evaluating CAB frequencies in double mutants carrying aur-A949 mutation combined to mutations in genes related to DNA damage response (DDR). We found that mutations in tefu (ATM) and in the histone variant H2Av were epistatic over aur-A949 indicating that Aur-A works in DDR and that it is required for γ-H2Av foci dissolution. More interestingly, we found that a mutation in lig4, a gene belonging to the non-homologous end joining (NHEJ) repair pathway, was epistatic over aur-A949. Based on studies in other systems, which show that phosphorylation is important to target Lig4 for degradation, we hypothesized that in aur-A949 mutant cells, there is a persistence of Lig4 that could be, in the end, responsible for CABs. Finally, we observed a synergistic interaction between Aur-A and the homologous recombination (HR) repair system component Rad 51 in the process that converts chromatid deletions into isochromatid deletions. Altogether, these data indicate that Aur-A depletion can elicit chromosome damage. This conclusion should be taken into consideration, since some anticancer therapies are aimed at reducing Aurora-A expression.
KeywordsAurora-A Chromosome aberrations Ligase 4 Rad 51 Drosophila
We thank D. M. Glover for the anti-Aurora-A antibody, T. Schüpbach for the brca2 mutant alleles, and J. A. Knoblich for UAS GFP Aur-A fly stock.
EM and AC performed research; CM and IS contributed to the design of the experiments and to the writing of the manuscript; and FV designed the experiments and wrote the manuscript.
This work was funded by Progetto di Ateneo (Sapienza University of Rome) to FV and by Progetto Avvio alla Ricerca (Sapienza University of Rome) to CM.
Compliance with ethical standards
Research involving human participants and/or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
Conflict of interest
The authors declare that they have no conflict of interest.
All data generated or analyzed during this study are included in this published article (and its supplementary information files).
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