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 i...
| Main Authors: | , , , , |
|---|---|
| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2021
|
| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/151271 |
| _version_ | 1811691742182768640 |
|---|---|
| author | Merigliano, Chiara Mascolo, Elisa Cesta, Anthony Saggio, Isabella Vernì, Fiammetta |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Merigliano, Chiara Mascolo, Elisa Cesta, Anthony Saggio, Isabella Vernì, Fiammetta |
| author_sort | Merigliano, Chiara |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:24:43Z |
| format | Journal Article |
| id | ntu-10356/151271 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:24:43Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | ntu-10356/1512712021-06-09T05:50:22Z A new role for Drosophila Aurora-A in maintaining chromosome integrity Merigliano, Chiara Mascolo, Elisa Cesta, Anthony Saggio, Isabella Vernì, Fiammetta School of Biological Sciences Science::Biological sciences Aurora-A Chromosome Aberrations 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. 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. 2021-06-09T05:50:22Z 2021-06-09T05:50:22Z 2019 Journal Article Merigliano, C., Mascolo, E., Cesta, A., Saggio, I. & Vernì, F. (2019). A new role for Drosophila Aurora-A in maintaining chromosome integrity. Chromosoma, 128(1), 41-52. https://dx.doi.org/10.1007/s00412-018-00687-0 0009-5915 https://hdl.handle.net/10356/151271 10.1007/s00412-018-00687-0 30612150 2-s2.0-85059522210 1 128 41 52 en Chromosoma © 2019 Springer-Verlag GmbH Germany, part of Springer Nature. All rights reserved. |
| spellingShingle | Science::Biological sciences Aurora-A Chromosome Aberrations Merigliano, Chiara Mascolo, Elisa Cesta, Anthony Saggio, Isabella Vernì, Fiammetta A new role for Drosophila Aurora-A in maintaining chromosome integrity |
| title | A new role for Drosophila Aurora-A in maintaining chromosome integrity |
| title_full | A new role for Drosophila Aurora-A in maintaining chromosome integrity |
| title_fullStr | A new role for Drosophila Aurora-A in maintaining chromosome integrity |
| title_full_unstemmed | A new role for Drosophila Aurora-A in maintaining chromosome integrity |
| title_short | A new role for Drosophila Aurora-A in maintaining chromosome integrity |
| title_sort | new role for drosophila aurora a in maintaining chromosome integrity |
| topic | Science::Biological sciences Aurora-A Chromosome Aberrations |
| url | https://hdl.handle.net/10356/151271 |
| work_keys_str_mv | AT meriglianochiara anewrolefordrosophilaauroraainmaintainingchromosomeintegrity AT mascoloelisa anewrolefordrosophilaauroraainmaintainingchromosomeintegrity AT cestaanthony anewrolefordrosophilaauroraainmaintainingchromosomeintegrity AT saggioisabella anewrolefordrosophilaauroraainmaintainingchromosomeintegrity AT vernifiammetta anewrolefordrosophilaauroraainmaintainingchromosomeintegrity AT meriglianochiara newrolefordrosophilaauroraainmaintainingchromosomeintegrity AT mascoloelisa newrolefordrosophilaauroraainmaintainingchromosomeintegrity AT cestaanthony newrolefordrosophilaauroraainmaintainingchromosomeintegrity AT saggioisabella newrolefordrosophilaauroraainmaintainingchromosomeintegrity AT vernifiammetta newrolefordrosophilaauroraainmaintainingchromosomeintegrity |