DNA-PKcs

DNA-PKcs

DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) is a crucial enzyme in the DNA repair process, specifically involved in the non-homologous end joining (NHEJ) pathway. It is a member of the PI3/PI4-kinase family and plays a significant role in maintaining genomic stability by repairing double-strand breaks (DSBs) in DNA.

Structure

DNA-PKcs is a large protein with a molecular weight of approximately 469 kDa. It is composed of several domains, including a kinase domain, a FAT domain, and a FATC domain. The kinase domain is responsible for its enzymatic activity, while the FAT and FATC domains are involved in protein-protein interactions and regulation of its activity.

Function

DNA-PKcs is primarily known for its role in the NHEJ pathway of DNA repair. Upon the occurrence of a DSB, DNA-PKcs is recruited to the site of damage by the Ku heterodimer, which consists of Ku70 and Ku80. The binding of the Ku heterodimer to DNA ends facilitates the recruitment and activation of DNA-PKcs.

Once activated, DNA-PKcs phosphorylates several substrates, including itself, Ku proteins, and other factors involved in the NHEJ pathway. This phosphorylation is crucial for the processing and ligation of DNA ends, ultimately leading to the repair of the break.

Clinical Significance

Mutations or deficiencies in DNA-PKcs can lead to increased sensitivity to ionizing radiation and a higher propensity for genomic instability, which is a hallmark of cancer. DNA-PKcs is also a target for cancer therapy, as inhibiting its activity can enhance the effectiveness of radiotherapy and certain chemotherapeutic agents.

Research and Therapeutic Implications

Research into DNA-PKcs has provided insights into its potential as a therapeutic target. Inhibitors of DNA-PKcs are being developed and tested in clinical trials for their ability to sensitize cancer cells to DNA-damaging agents. Understanding the precise mechanisms of DNA-PKcs in DNA repair and its interactions with other proteins is crucial for developing effective therapies.

Also see

• DNA repair
• Non-homologous end joining
• Ku heterodimer
• PI3/PI4-kinase family
• Genomic instability