n response to DNA damage in G2, mammalian cells must avoid entry into mitosis and instead initiate DNA repair. Here, we show that, in response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/CCdh1, with the consequent degradation of Plk1, a prominent mitotic kinase. This process induces the stabilization of Claspin, an activator of the DNA-damage check- point, and Wee1, an inhibitor of cell-cycle progres- sion, and allows an efficient G2 checkpoint. As a by-product of APC/CCdh1 reactivation in DNA-dam- aged G2 cells, Claspin, which we show to be an APC/ CCdh1 substrate in G1, is targeted for degradation. However, this process is counteracted by the deubi- quitylating enzyme Usp28 to permit Claspin-medi- ated activation of Chk1 in response to DNA damage. These findings define a novel pathway that is crucial for the G2 DNA-damage-response checkpoint.

The Cdc14B-Cdh1-Plk1 Axis Controls the G2 DNA-Damage-Response Checkpoint

Guardavaccaro, Daniele;
2008-01-01

Abstract

n response to DNA damage in G2, mammalian cells must avoid entry into mitosis and instead initiate DNA repair. Here, we show that, in response to genotoxic stress in G2, the phosphatase Cdc14B translocates from the nucleolus to the nucleoplasm and induces the activation of the ubiquitin ligase APC/CCdh1, with the consequent degradation of Plk1, a prominent mitotic kinase. This process induces the stabilization of Claspin, an activator of the DNA-damage check- point, and Wee1, an inhibitor of cell-cycle progres- sion, and allows an efficient G2 checkpoint. As a by-product of APC/CCdh1 reactivation in DNA-dam- aged G2 cells, Claspin, which we show to be an APC/ CCdh1 substrate in G1, is targeted for degradation. However, this process is counteracted by the deubi- quitylating enzyme Usp28 to permit Claspin-medi- ated activation of Chk1 in response to DNA damage. These findings define a novel pathway that is crucial for the G2 DNA-damage-response checkpoint.
2008
DNA damage response; ubiquitin, cell cycle
File in questo prodotto:
File Dimensione Formato  
Bassermann Cell 2008.pdf

accesso aperto

Tipologia: Versione dell'editore
Licenza: Dominio pubblico
Dimensione 1.48 MB
Formato Adobe PDF
1.48 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/992867
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 334
  • ???jsp.display-item.citation.isi??? 329
social impact