From Nuclear Condensates to DNA Repair: Probing PTK2 Dynamics under Genotoxic Stress

Cardiovascular complications arising from antineoplastic therapies have become an emerging public health issue due to the growing population of cancer survivors. Cardiotoxicity induced by chemotherapeutic agents widely used for various malignancies, such as doxorubicin (DOX), is a severe condition that can progress to chronic cardiomyopathy, congestive heart failure, and death. To counteract this damage, cardiomyocytes rely on complex nuclear signaling pathways, where Protein Tyrosine Kinase 2 (PTK2) plays a role in regulating essential cellular functions, including survival, through the modulation of p53 levels and the PI3K/AKT pathway. Our research has focused on investigating the dynamics of nuclear PTK2 under doxorubicin stress using super-resolution microscopy and single-molecule techniques. Our results reveal that PTK2 is sequestered into Bclaf1 biomolecular condensates and protected from ubiquitin-mediated degradation. Furthermore, we demonstrate that PTK2 co-localizes with p68 in biomolecular condensates, where its kinase activity is required to assemble the p68/β-catenin complex, thereby driving pro-survival transcriptional programming. Notably, we observed that PTK2 interacts with PARP1 during the DNA damage response. Specifically, we show that PTK2 binds to PARylated proteins and we found evidence that PTK2 itself might be PARylated. These findings provide novel insights into the molecular mechanisms underlying PTK2 function to enhance cellular resistance to genotoxic stress 

This work was supported by the São Paulo Research Foundation (FAPESP #2018/07383-6 and #2020/11824-8) and he Fundação de Desenvolvimento da UNICAMP (FUNCAMP) (2545/23)