Abstract

To identify new regulators of homologous recombination (HR) repair we carried out a genome wide siRNA screen combined with ionizing irradiation (IR) using RAD51 foci formation as readout. All candidates were confirmed by independent siRNAs and validated in secondary assays like HR activity and RPA foci formation. Network analysis of the top modifiers identified gene clusters involved in HR as well as components of the Ribosome, the Proteasome and the
Spliceosome, which are known to be required for effective DNA repair. We identified and characterized the RNA Polymerase II associated protein CDC73/Parafibromin as a new player in HR and show that it is critical for genomic stability. CDC73 interacts with components of the SCF/Cullin and INO80/NuA4 chromatin remodeling complexes to promote Histone ubiquitination. Our findings indicate that CDC73 is involved in local chromatin decondensation at sites of DNA damage to promote DNA repair. This function of CDC73 is related to but independent of its role in transcriptional elongation.