Fanconi anemia (FA) is a congenital disease characterized by bone marrow failure, increased cancer risk and hypersensitivity to DNA cross-linking agents, implying a role for this pathway in the maintenance of genomic stability. The central player of the FA pathway is the multi-subunit E3 ubiquitin ligase complex that is activated through a replication and DNA-damage dependent mechanism. A consequence of the activation of the complex is the monoubiquitination of FANCD2 and FANCI, late term effectors in the maintenance of genome integrity. We find that PSF2 and CSN3 interact with the core complex subunit FANCF in a yeast two-hybrid system. PSF2 is a member of the GINS complex, which is essential both for the initiation and elongation steps of DNA replication. CSN3 is a subunit of the COP9 signalosome (CSN), the regulator of cullin-based ubiquitin ligases. These interactions have been confirmed by co-immunoprecipitation in human cells. We observed a decreased binding to chromatin of the FA core complex in HeLa cells depleted for PSF2, suggesting that the GINS complex may have a role in either loading or stabilizing the FA core complex onto chromatin. However, depletion of PSF2 did not reduce monoubiquitination of FANCD2 or its localization to nuclear foci following DNA damage. On the contrary, depletion of the CSN leads to an increase of monoubiquitinated FANCD2 in normal growth conditions. Our results suggest that PSF2 and CSN3 are novel interacting proteins of the FA core complex.
|Titolo:||PSF2 and COPS3 are novel interactors of the Fanconi anemia core complex|
|Supervisori e coordinatori interni:||MANTOVANI, ROBERTO|
|Data di pubblicazione:||12-apr-2010|
|Parole Chiave:||Fanconi anemia ; ICL repair ; GINS ; COP9 signalosome|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Citazione:||PSF2 and COPS3 are novel interactors of the Fanconi anemia core complex ; tutor: F. Marini ; coordinatore: R. Mantovani. - Milano : Università degli studi di Milano. DIPARTIMENTO DI SCIENZE BIOMOLECOLARI E BIOTECNOLOGIE, 2010 Apr 12. ((22. ciclo, Anno Accademico 2008/2009.|
|Appare nelle tipologie:||13 - Tesi di dottorato discussa entro ottobre 2010|