While in vitro experiments emphatically demonstrated the inhibitory effect of p21 on PCNA dependent DNA replication and repair it was much harder to arrive to similar conclusions in experiments performed in cells. This might depend, at least in part, on the convergent signals that prevent p21 up-regulation in S phase. We have come across the intriguing observation that a number of genotoxic treatments that induce transient or permanent arrest in S phase coordinately promote p21 down-regulation and PCNA ubiquitination. Moreover, stable p21 expression negatively modulates PCNA ubiquitination, a post-transcriptional modification of the sliding clamp relevant for its DNA repair-related activities. This observation prompt us to the study of novels aspects of PCNA regulation by p21. We propose to explore the mechanisms for p21 dependent inhibition of PCNA ubqiutination after UV irradiation. This will also facilitate the identification of other molecules that modulate PCNA ubiquitination and are targets of p21. The link between p21 degradation and PCNA ubiquitination will also allow the identification of pathways upstream that coordinate these events. The effects on cell survival of a stable p21 expression during the above mentioned genotoxic treatments might reveal the biological relevance of p21 down-regulation and might be significant for cancer therapy.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
5R03TW007440-02
Application #
7325755
Study Section
International and Cooperative Projects - 1 Study Section (ICP1)
Program Officer
Katz, Flora N
Project Start
2006-12-01
Project End
2009-11-30
Budget Start
2007-12-15
Budget End
2008-11-30
Support Year
2
Fiscal Year
2008
Total Cost
$39,372
Indirect Cost
Name
Columbia University (N.Y.)
Department
Biology
Type
Other Domestic Higher Education
DUNS #
049179401
City
New York
State
NY
Country
United States
Zip Code
10027
Soria, Gastón; Gottifredi, Vanesa (2010) PCNA-coupled p21 degradation after DNA damage: The exception that confirms the rule? DNA Repair (Amst) 9:358-64
Prives, Carol; Gottifredi, Vanesa (2008) The p21 and PCNA partnership: a new twist for an old plot. Cell Cycle 7:3840-6
Soria, Gaston; Speroni, Juliana; Podhajcer, Osvaldo L et al. (2008) p21 differentially regulates DNA replication and DNA-repair-associated processes after UV irradiation. J Cell Sci 121:3271-82