USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110
<p style="text-align:justify;"> Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regu...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2013
|
| _version_ | 1797071458108702720 |
|---|---|
| author | Li, J D'Angiolella, V Seeley, E Kim, S Kobayashi, T Fu, W Campos, E Pagano, M Dynlacht, B |
| author_facet | Li, J D'Angiolella, V Seeley, E Kim, S Kobayashi, T Fu, W Campos, E Pagano, M Dynlacht, B |
| author_sort | Li, J |
| collection | OXFORD |
| description | <p style="text-align:justify;"> Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regulates centriole duplication while restricting centriole elongation and ciliogenesis. Maintenance of normal CP110 levels is essential, as excessive CP110 drives centrosome over-duplication and suppresses ciliogenesis, whereas its depletion inhibits centriole amplification and leads to highly elongated centrioles and aberrant assembly of cilia in growing cells1,2. CP110 levels are tightly controlled, partly through ubiquitination by the ubiquitin ligase complex SCFcyclin F during G2 and M phases of the cell cycle3. Here, using human cells, we report a new mechanism for the regulation of centrosome duplication that requires USP33, a deubiquitinating enzyme that is able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily in S and G2/M phases, the periods during which centrioles duplicate and elongate. USP33 potently and specifically deubiquitinates CP110, but not other cyclin-F substrates. USP33 activity antagonizes SCF<sup>cyclin F</sup>-mediated ubiquitination and promotes the generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, we have identified the first centriolar deubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin-F-mediated destruction of a key substrate. Our results point towards potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification. </p> |
| first_indexed | 2024-03-06T22:53:32Z |
| format | Journal article |
| id | oxford-uuid:5f9a2b15-f641-4b42-ba40-82617652513b |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:53:32Z |
| publishDate | 2013 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:5f9a2b15-f641-4b42-ba40-82617652513b2022-03-26T17:48:02ZUSP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5f9a2b15-f641-4b42-ba40-82617652513bEnglishSymplectic Elements at OxfordSpringer Nature2013Li, JD'Angiolella, VSeeley, EKim, SKobayashi, TFu, WCampos, EPagano, MDynlacht, B <p style="text-align:justify;"> Centrosome duplication is critical for cell division, and genome instability can result if duplication is not restricted to a single round per cell cycle. Centrosome duplication is controlled in part by CP110, a centriolar protein that positively regulates centriole duplication while restricting centriole elongation and ciliogenesis. Maintenance of normal CP110 levels is essential, as excessive CP110 drives centrosome over-duplication and suppresses ciliogenesis, whereas its depletion inhibits centriole amplification and leads to highly elongated centrioles and aberrant assembly of cilia in growing cells1,2. CP110 levels are tightly controlled, partly through ubiquitination by the ubiquitin ligase complex SCFcyclin F during G2 and M phases of the cell cycle3. Here, using human cells, we report a new mechanism for the regulation of centrosome duplication that requires USP33, a deubiquitinating enzyme that is able to regulate CP110 levels. USP33 interacts with CP110 and localizes to centrioles primarily in S and G2/M phases, the periods during which centrioles duplicate and elongate. USP33 potently and specifically deubiquitinates CP110, but not other cyclin-F substrates. USP33 activity antagonizes SCF<sup>cyclin F</sup>-mediated ubiquitination and promotes the generation of supernumerary centriolar foci, whereas ablation of USP33 destabilizes CP110 and thereby inhibits centrosome amplification and mitotic defects. To our knowledge, we have identified the first centriolar deubiquitinating enzyme whose expression regulates centrosome homeostasis by countering cyclin-F-mediated destruction of a key substrate. Our results point towards potential therapeutic strategies for inhibiting tumorigenesis associated with centrosome amplification. </p> |
| spellingShingle | Li, J D'Angiolella, V Seeley, E Kim, S Kobayashi, T Fu, W Campos, E Pagano, M Dynlacht, B USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 |
| title | USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 |
| title_full | USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 |
| title_fullStr | USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 |
| title_full_unstemmed | USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 |
| title_short | USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110 |
| title_sort | usp33 regulates centrosome biogenesis via deubiquitination of the centriolar protein cp110 |
| work_keys_str_mv | AT lij usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT dangiolellav usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT seeleye usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT kims usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT kobayashit usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT fuw usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT campose usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT paganom usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 AT dynlachtb usp33regulatescentrosomebiogenesisviadeubiquitinationofthecentriolarproteincp110 |