THE PAGANO LABORATORY
DNA DAMAGE RESPONSE R E S E A R C H

Genome integrity is achieved by the action of multiple DNA Damage Sensors and Repair Factors that aim correcting unintended insults, which may otherwise lead to deleterious mutations.  In the past, we defined a role for the CDC14B-CDH1-PLK1 and the CHK1-β-TrCP-CDC25A axes in the DNA damage response, and demonstrated that, upon DNA replication stress, FBH1 promotes double-strand break formation and cell death.  The conversion of ribonucleotides to deoxyribonucleotides represents one necessary event for the proper induction of replicative and repair DNA synthesis. Previous work from our lab has uncovered a role for cyclin F in regulating the levels of the ribonucleotide reductase subunit RRM2.  This event controls the cellular abundance of dNTPs and ensures efficient DNA repair in response to genotoxic stress.  We also found that cyclin F-mediated degradation of SLBP limits the synthesis of H2A.X during the recovery from genotoxic stress.  Moreover, we found that the Integrator complex regulates the response to DNA damage and promotes processing of canonical histone mRNAs.  We also uncovered an important function for the PARP1-TIMELESS complex in activating the DNA damage response and recruiting the ncPRC1.1 complex to DNA lesions to repress transcription.  Currently, we are investigating how cyclins and the SCF complex control homologous recombination repair.

 

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