The Role of Cyclophilin A in DNA Repair

Conceitos essenciais

Cyclophilin A plays a crucial role in DNA repair, impacting genomic stability and influencing homologous recombination repair following replication fork stalling.

Resumo

The study explores the impact of Cyclophilin A (CYPA) on DNA repair mechanisms, focusing on its interaction with the MRN complex and its involvement in homologous recombination repair (HRR). The research reveals that CYPA loss or inhibition impairs HRR following DNA replication fork stalling, leading to genomic instability. Through various experiments involving CRISPR/Cas9-engineering, siRNA, BioID, co-immunoprecipitation, and pathway-specific investigations, the study uncovers novel insights into CYPA biology. It demonstrates that CYPA interacts with components of the DNA end resection machinery and directly interacts with NBS1 from the MRN complex. Additionally, the research identifies genetic vulnerabilities associated with CYPA loss and inhibition, suggesting potential applications for targeting cancer cells with shared genomic instability profiles. Overall, the findings highlight the critical role of CYPA in DNA repair processes.

Estatísticas

CsA induces DSBs in LIG4 syndrome patient fibroblasts.
CsA treatment impairs NHEJ, SSA, and HRR pathways.
Treatment with NIM811 results in more significant reductions in SSA and HRR compared to CsA.

Citações

"Cylophilin A loss or inhibition impairs Homologous Recombination Repair following DNA replication fork stalling."
"CsA-induced DSBs are observed in LIG4 syndrome patient fibroblasts."
"Cylophilin A interacts with components of the DNA end resection machinery."

Principais Insights Extraídos De

A novel role for the peptidyl-prolyl cis-trans isomerase Cyclophilin A in DNA-repair following replication fork stalling via the MRE11-RAD50-NBS1 complex

by Bedir,M., Ou... às www.biorxiv.org 06-28-2023

https://www.biorxiv.org/content/10.1101/2023.06.27.546694v1

Perguntas Mais Profundas

How can targeting Cyclophilin A be utilized as a potential strategy for cancer treatment?

Cyclophilin A (CYPA) has been identified as playing a crucial role in DNA repair, particularly in homologous recombination repair (HRR), following replication fork stalling. Inhibition or loss of CYPA impairs HRR and other DNA repair pathways, leading to genomic instability and increased sensitivity to DNA damage-inducing agents like Cyclosporin A (CsA). This vulnerability can be exploited in cancer cells with high levels of genomic instability, such as those with deficiencies in key DNA repair genes. By targeting CYPA using specific inhibitors, it may be possible to selectively kill cancer cells while sparing normal cells that have intact DNA repair mechanisms.

What are the implications of inhibiting Cyclophilin A on normal cellular functions beyond DNA repair?

While the primary focus of inhibiting Cyclophilin A is on its role in DNA repair and genome stability, there may be broader implications on normal cellular functions. CYPA is involved in various processes beyond DNA repair, including protein folding regulation and RNA metabolism. Inhibiting CYPA's peptidyl-prolyl cis-trans isomerase (PPI) activity could disrupt these essential cellular processes, potentially leading to misfolded proteins, altered RNA processing, and perturbed signaling pathways. These disruptions could impact cell viability and function beyond just the realm of DNA repair.

How does understanding Cyclophilin A's role in DNA repair contribute to advancements in personalized medicine?

Understanding the intricate involvement of Cyclophilin A in regulating critical aspects of the DNA damage response pathway provides valuable insights for personalized medicine approaches. By elucidating how CYPA influences specific steps within the complex network of DSB repairs like HRR or NHEJ, clinicians can tailor treatment strategies based on an individual's genetic profile related to these pathways. For instance:

Patients with mutations affecting components interacting with CYPA might benefit from alternative treatments.
Targeting CYPA inhibition could be considered for cancers exhibiting vulnerabilities due to defective DSB repairs.
This knowledge allows for more precise therapeutic interventions that consider each patient's unique genetic makeup and disease characteristics when designing treatment plans tailored specifically to their needs.