The role of NUDT16 in DNA damage response and tumorigenesis

Project Summary The DNA damage-signaling pathways play critical roles in maintaining genomic stability following DNA damage. Disruption of these pathways leads to genomic instability and increased cancer incidence, suggesting that these pathways are essential for the prevention of neoplastic transformation. Our recent work demonstrated that NUDT16’s catalytic hydrolase activity is required for 53BP1 de-ADP-ribosylation, 53BP1 protein stability, and its function in cell survival. An important question remains of whether other critical unidentified substrate proteins exist for NUDT16 hydrolase activity. Our preliminary data revealed that NUDT16 loss decreased the level of multiple DNA damage checkpoint and repair protein. Moreover, cells lacking NUDT16 showed significant DNA repair defects and chromosomal aberrations. In addition, Nudt16-/- mice presents increased spleen weight and elevated number of splenic follicles. Driven by these promising preliminary results, in this renewal application, we hypothesize that NUDT16, through its catalytic activity, regulates multiple DNA damage checkpoint and repair proteins, to facilitate DNA end resection-initiated HR repair, which is critical for the maintenance of genomic stability and prevention of tumorigenesis. We will pursue the following Specific Aims: Aim 1: Determine the role(s) of NUDT16 in regulation of the DNA repair pathways. Aim 2: Define the physiological function of Nudt16 in vivo. Aim 3: Investigate the underlying mechanisms by which Nudt16 loss contributes to lymphomagenesis in mice. Taken together, these in-depth studies focused on NUDT16 not only contribute significantly to our understanding of the complex regulation of DNA repair pathways but may also provide critical insights into the underlying mechanisms by which loss of Nudt16 contributes to tumorigenesis in mice.