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Emmanuele Crespan


 

IGM-CNR, Via Abbiategrasso, 207 - 27100 Pavia, Italy

tel: +39-0382-546346

fax: +39-0382-422286 

E-mail: crespanigm.cnr.it

http://www.igm.cnr.it/

 

Curriculum vitae

2004. Degree in Biological Sciences at the University of Pavia. 

2008. PhD degree in Genetic and biomolecular Science. Department of Genetics and Microbiology, University of Pavia 

2008-2011. Post-doctoral fellow, Italian Federation for Cancer Research  - FIRC. Institute of Molecular Genetics (IGM-CNR), Pavia. 

(2009). Visiting researcher at University of Zurich, Institute of Veterinary Biochemistry and Molecular Biology.

 

Awards

2008. Milano, Carlo Erba Foundation. Winner of the Cecilia Cioffrese Award for excellence in scientific research. 

2015. Roma, CNR. Young Researcher Scientific Award. 


Research Activity

Dr. Crespan has focused his attention on the enzymatic characterization of reparative DNA polymerases beta and lambda. These enzymes are involved in different DNA repair pathways as response to different kind of lesions, including oxidative damages that are induced by reactive oxygen species.

Among those lesions, the most important is the oxidation of the guanine base (G) in position 8 (oxoG). Contrary to the normal G, this oxidize base can pairs, beside than toward the canonical cytidine (C), also pair with the adenine base (A). As a consequence, both replicative and translesion polymerases incorporate with the same efficiency either A or C opposite oxoG. The A:oxoG pairing leads, in the following replication round, to the acquisition of the mutation, a C->T transversion.

In normal cells, about oxoG are formed every day. To avoid the insertion of mispaired nucleotides, the recruitment of a faithful polymerase, able to incorporate the correct C opposite the lesion, is thus necessary. Since such a polymerases was not known, it was believed that this repair pathway was inefficient, involving multiple round of futile cycle of re-incorporation of A opposite the lesion:

In our lab we demonstrated, for the first time, that polλ, coordinated by PCNA and RP-A, can efficiently perform a faithful synthesis opposite oxoG. We also found that this mechanism was conserved also toward other oxidize bases such as 2-OH-A.

Pol lambda is also involved in the non-homologous end joining repair pathway (NHEJ). NHEJ involved the recruitment of Ku70/80 and DNA-PKs factors at the DNA broken ends. However, several findings suggest that in the absence of those factors, alternative end joining pathways (A-EJ) emerged to seal the lesion. In one of these pathways, the Micro-homology Mediated End Joining (MMEJ), the formation of a micro-homology region of 4-25nt at the broken ends is required. Using DNA substrates that mimic DNA double strand breaks (DSBs) with a terminal micro-homology (4-5nt) region, we found that polλ was necessary and sufficient to bridge and extend the broken ends, suggesting a crucial role of polλ in the MMMEJ pathway

Our interest is now focused on the study of the interactions between pol lambda and the other factors involved in NHEJ and A-EJs pathways. We observed that in different cell lines, the silencing of Ku70/80 and DNA-PKs did not caused a reduction of cell viability even when DSBs damage was administered. However, the concomitant silencing of one of these factor together with pol lambda, strongly impaired cell viability leading to synthetic lethality. If confirmed, such data could suggest new therapeutic strategies in the fighting of cancer, especially of those malignancies that lost the ability to repair DSBs through homologous recombination. 

 

 

Publications

Dr. Crespan is author/co-author of more than 50 publications in international peer-reviewed 

 

h-index 16 (Google Scholar)

 

ORCID ID: 0000-0003-0597-6929


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