ADP-ribosylation at the nuclear pore complex

• Applicant: Dr. Orsolya Leidecker
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 524909464

My group is interested in two cellular processes that are often deregulated during aging and in aging-associated diseases, such as cancer: genome stability maintenance and trafficking through the nuclear pore complex (NPC). Under physiological conditions, genome stability is preserved by an intricate network of DNA repair pathways that are tightly controlled by posttranslational modifications (PTMs), such as PARP1-mediated ADP-ribosylation(ADPr). The NPC is another significant contributor to genome integrity maintenance, however, whether ADPr also controls the functions of the NPC and its components, the nucleoporins, is not known. In recent years, I contributed significantly to our understanding of the molecular basis of ADPr, which has historically been a challenging PTM to study. I pioneered the identification of physiological PARP1 modifications on histones upon DNA damage by mass spectrometry and unveiled serine as the primary acceptor site for PARP1’s enzymatic activity (Ser-ADPr). Moreover, I developed a versatile platform of peptide- and antibody-based tools to investigate site-and substrate-specific ADPr. These significant advances enable us now to study ADPr on diverse cellular substrates, including nucleoporins. My group will build on this to identify novel regulators of DNA repair among ADPr substrates and enzymes at the nuclear periphery. Moreover, we will establish a crosstalk between NPC biology and PARP1 signaling by determining the extent and means of NPC regulation by Ser-ADP, using state-of-the-art proteomics and microscopy-based approaches. Since my versatile platform of ADPr tools enables us to study modifications beyond PARP1-mediated Ser-ADPr, we will also focus on PARP11, an elusive enzyme that specifically localizes to the nuclear periphery. We aim to advance our understanding of the molecular details of how PARP11 regulates NPC biology, from nucleocytoplasmic trafficking to DNA repair. Our studies have the potential to provide a detailed mechanistic rationale for modulating NPC biology through the ADPr signaling pathway and targetable PARP enzymes, with great translational potential for the treatment of cancer or other aging-associated diseases that exploit dysregulation of the NPC or DNA repair pathways.

• DFG Programme: Independent Junior Research Groups