Leidecker Laboratory

Maintenance of Genome Stability, Nuclear Integrity, and Immune Regulation

Genome stability maintenance and the functions of the nuclear pore complex (NPC) are critical for cellular health and are often deregulated during aging and in age-associated diseases, such as cancer. Under normal physiological conditions, genome integrity is preserved by an intricate network of DNA repair pathways that are tightly regulated by posttranslational modifications (PTMs), including PARP1-mediated ADP-ribosylation (ADPr). The NPC also plays a vital role in maintaining genome stability; however, how ADPr and PARP enzymes influence NPC functions and whether they intersect with immune regulatory processes remains an exciting frontier to explore.

Recent evidence has begun to reveal that certain PARPs, particularly PARP11, are expressed in immune cells and modulate immune responses. This suggests a complex interplay where nuclear dynamics, DNA repair, and immunity are interconnected, especially at the nuclear periphery, which is a hub for both cellular stress responses and immune regulation.

Research Focus

Our research centers on two cellular processes often deregulated during aging and disease:

• Genome stability maintenance
• Trafficking through the nuclear pore complex

Additionally, we are expanding our investigations to include the emerging roles of PARP enzymes in immune cell regulation. Recent findings indicate that PARP11 may serve as a crucial link between nuclear processes and immune signaling, orchestrating cellular responses to stress and infection. We aim to elucidate in an interdisciplinary approach how PARP-mediated ADP-ribosylation influences immune cell functions and how these modifications interface with NPC activity and genome integrity.

Research Goals

Building on recent advances, such as the identification of physiologically relevant PARP1 modifications on histones, our group aims to:

• Identify new regulators of DNA repair among ADPr substrates and enzymes at the nuclear periphery.
• Unravel the crosstalk between NPC biology, PARP1 signaling, and immune responses, employing cutting-edge proteomics and microscopy.
• Investigate the functional roles of PARP11 at the nuclear periphery, focusing on its impact on NPC functions and immune cell activity, and how PARP11-mediated ADPr influences immune regulation alongside genome maintenance.

By integrating insights from DNA repair and immune modulation, we seek to develop a comprehensive understanding of how PARPs coordinate nuclear integrity, cellular stress responses, and immunity, opening new therapeutic perspectives across multiple aging- and disease-related contexts.

Figure: Our lab logo encompasses the structure or ADP-ribose and some of the cellular processes we are investigeting in context of this modifcation: protein modifications, DNA repair, NPC and immunity.