Genome stability maintenance and the functions of the nuclear pore complex (NPC) are often deregulated during aging and in aging-associated diseases, such as cancer. 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.
We focus on two cellular processes that are often deregulated during aging and in aging-associated diseases, such as cancer:
Our group addresses several outstanding questions regarding the posttranslational modifications (PTMs) that regulate NPC functions and the contribution of the individual NPC components to DNA repair, both within the NPC and outside of it. We focus particularly on ADP-ribosylation (ADPr), that is catalyzed by the biomedically important and aging-relevant enzyme, PARP1, an integrated early stress responder to DNA damage; and on PARP11, an elusive enzyme that specifically localizes to the nuclear periphery.
In recent years, Orsolya Leidecker contributed significantly to our understanding of the molecular basis of ADPr. As a postdoc, she pioneered the identification of physiological PARP1 modifications on histones upon DNA damage by mass spectrometry and developed a versatile platform of peptide- and antibody-based tools to investigate site-and substrate-specific ADPr.
These studies have the potetial 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.