XRCC6

XRCC6 Full Name

X-ray repair complementing defective repair in Chinese hamster cells 6

XRCC6 Introduction

The XRCC6 gene, located on chromosome 22q13.2, encodes a protein essential for the survival of eukaryotic cells. Historically known as Ku70, this protein functions as a critical tool in the cellular toolkit for identifying and repairing broken DNA strands. By acting as a high-affinity sensor for physical damage within the nucleus, XRCC6 ensures that the genetic blueprint remains intact during the rigors of environmental stress and metabolic activity.

Figure 1. Strcuture of XRCC6.

Core Function in DNA Double-Strand Break Repair
XRCC6 (X-ray repair cross complementing 6) encodes the 70 kDa subunit of the Ku heterodimer, known as Ku70, which serves as the essential DNA-binding component of the non-homologous end joining (NHEJ) pathway. Upon detection of DNA double-strand breaks, the Ku70/Ku80 heterodimer rapidly recognizes and binds to the broken DNA ends with high affinity, forming a ring-shaped structure that encircles the DNA duplex. This binding stabilizes the broken ends and recruits the catalytic subunit DNA-PKcs, activating its kinase activity and subsequently assembling the downstream ligation machinery required for end joining. Beyond its well-established role in NHEJ, XRCC6 also exhibits 5'-deoxyribose-5-phosphate lyase activity, enabling it to process damaged DNA termini before ligation, and functions as an ATP-dependent DNA helicase with 3'-5' directionality.

Regulation of Protein Stability and Therapeutic Targeting
Recent research has uncovered sophisticated regulatory mechanisms controlling XRCC6 protein stability with direct therapeutic implications. The E3 ubiquitin ligase TRIM21 mediates K48-linked polyubiquitination of XRCC6 at lysine 526, targeting it for proteasomal degradation. This degradation is counteracted by CNOT7, which interacts with XRCC6 to stabilize its protein levels by inhibiting TRIM21-mediated ubiquitination, thereby enhancing NHEJ repair efficiency. In colorectal cancer, elevated CNOT7 expression correlates with radiotherapy resistance through this mechanism, and targeting the XRCC6/XRCC5 heterodimer with the inhibitor STL127705 in combination with radiation significantly suppresses tumor growth in patient-derived xenograft models. These findings position the CNOT7-TRIM21-XRCC6 axis as a promising therapeutic target for overcoming radioresistance.

Alternate Names for XRCC6

XRCC6; X-ray repair complementing defective repair in Chinese hamster cells 6; ML8; KU70; TLAA; CTC75; CTCBF; G22P1; X-ray repair cross-complementing protein 6; 5-dRP lyase Ku70; 5''-deoxyribose-5-phosphate lyase Ku70; 5''-dRP lyase Ku70; 70 kDa subunit o