P21Cip1/waf1 differentially regulates DNA replication and DNA repair-associated processes after UV

SORIA G; SPERONI J; BELLUSCIO L AND GOTTIFREDI V

Ventura, California, USA

Congreso; Gordon Conference:Mammalian DNA Repair; 2008

Gordon Research Conferences

En esta conferencia de alto prestigio internacional la presentación de datos tiene como condición ineludible que dichas observaciones no hayan sido publicadas. Para proteger la confidencialidad de dichos datos la política de estos congresos es la de  no generar libros de resúmenes. El abstract presentado por nuestro grupo se detalla a continuación. P21Cip1/waf1 differentially regulates DNA replication and DNA repair-associated processes after UV Gaston Soria, Juliana Speroni, Laura Belluscio and Vanesa Gottifredi1 Cell Cycle and Genomic Stability Laboratory. Fundación Instituto Leloir- CONICET, Universidad de Buenos Aires. Abstract Although p21 up-regulation is required to block cell cycle progression after many types of genotoxic insults, UV irradiation triggers p21 proteolysis. The significance of the increased p21 turnover is unclear and might be associated to DNA repair. While the role of p21 in Nucleotide Excision Repair (NER) remains controversial, recent reports explore its effect on Translesion DNA Synthesis (TLS), a process that avoids replication blockage during S phase. Herein we analyze the effect of p21 on different PCNA-driven processes including DNA replication, NER and TLS. Whereas only the CDK binding domain of p21 is required for cell cycle arrest in unstressed cells; neither the CDK- nor the PCNA-binding domains of p21 are able to block early and late steps of NER. Intriguingly, through its PCNA binding domain, p21 inhibited the recruitment of the TLS-polymerase, polh, to PCNA foci after UV. Moreover, this obstruction correlates with accumulation of gH2AX and increased apoptosis.  Taken together, these data suggest that increased p21 proteolysis after UV irradiation might be relevant for efficient by-pass of lesions by translesion polymerases. In the box below, please indicate your particular activities which justify favorable consideration of you as a participant and contributor to this Conference. This information is required I am a young independent researcher working in Argentina (South America) that has recently incursion in the DNA Repair field. I am certain that this Conference is perfect for my current research interests. During my post-doctoral experience (in Dr. Carol Prives’ laboratory at Columbia University) I demonstrated that the tumor suppressor p53, is transcriptionally impaired in its ability to induce the Cyclin dependent Kinase Inhibitor (CKI), p21, during DNA replication blockage [1]. We now know that this is due to the specific inhibition of p21 transcription at a post-initiation level [2]. We have also showed that p21 proteolysis is increased when cells accumulate in S phase as a result of genotoxic insult [3]. It has also been demonstrated that UV irradiation, which induces intra-S-phase checkpoint, upregulates p21 degradation. Therefore, through convergent mechanisms, p21 accumulation and cell cycle arrest are prevented in S phase [4].  After that post doctoral experience I moved back to Argentina and I focused on the biological significance of p21 downregulation during S phase and found out that p21 proteolysis is required for efficient ubiquitination of PCNA [5]. Herein we report the implication that our findings have on TLS and NER. I therefore think that my previous activities and my current contribution to this field justify my participation to the 2008 DNA Damage, Mutation and Cancer Gordon Research Conference. Most importantly, during the last 3 years I became more interested in the modulation of DNA repair through the cell cycle. Thus, being able to interact with at least 10 of the speakers of this meeting will be extremely inspiring for my future work. [1] Gottifredi V, Shieh S, Taya Y, Prives C. Proc Natl Acad Sci U S A 2001;98 (3):1036-41. [2] Mattia M. Gottifredi V, McKinney K., and Prives C. Mol Cell Biol 2006;in press. [3] Gottifredi V, McKinney K, Poyurovsky MV, Prives C. J Biol Chem 2004;279 (7):5802-10. [4] Gottifredi V, Prives C. Semin Cell Dev Biol 2005;16 (3):355-68. [5] Soria G, Podhajcer O, Prives C, Gottifredi V. Oncogene 2006;25 (20):2829-38.