Homeodomain protein PRRX1 anchors the Ku heterodimers at DNA double-strand breaks to promote nonhomologous end-joining.

ABSTRACT: The DNA-dependent protein kinase (DNA-PK) complex plays a critical role in nonhomologous end-joining (NHEJ), a template-independent pathway for repairing DNA double-strand breaks (DSBs). The association of Ku70/80 with DSB ends facilitates the assembly of the DNA-PK holoenzyme. However, key mechanisms underlying the attachment and stabilization of DNA-PK at broken DNA ends remain unclear. Here, we identify PRRX1, a homeodomain-containing protein, as a mediator of chromatin localization and subsequent activation of DNA-PK. PRRX1 oligomerizes to simultaneously bind to double-strand DNA and the SAP (SAF-A/B, Acinus, and PIAS) domain of Ku70, thereby enhancing Ku anchoring at DSBs and stabilizing DNA-PK for efficient NHEJ repair. Reduced expression or pathogenic mutations of PRRX1 are associat

SUBMITTER: Wang Y 

PROVIDER: S-EPMC11925728 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature