# O-GlcNAcylation of XRCC4 controls its stability and confers resistance to DNA double-strand break damage in cancer cells

## TL;DR

This study shows that a sugar modification on a DNA repair protein helps cancer cells resist DNA damage, suggesting new treatment strategies.

## Contribution

The novel finding is that O-GlcNAcylation at Thr308 stabilizes XRCC4, promoting cancer cell resistance to DNA damage.

## Key findings

- XRCC4 is O-GlcNAcylated at Thr308, which inhibits its degradation and increases its stability.
- O-GlcNAcylated XRCC4 enhances cancer cell resistance to DNA double-strand break damage.
- Modifying XRCC4's O-GlcNAcylation could improve cancer treatment responses to chemotherapy or radiotherapy.

## Abstract

X-ray repair cross-complementing protein 4 (XRCC4), a non-homologous end-joining protein involved in DNA double-strand break repair, is highly expressed in human cancer cells and tissues. A prior OGT interactome study identified XRCC4 as a candidate for O-GlcNAcylation. O-GlcNAcylation levels, a post-translational modification found on nuclear and cytosolic proteins, are also elevated in various cancers. However, the direct regulatory mechanism linking O-GlcNAcylation to XRCC4 function in cancer cells remains unclear. Here, we found that XRCC4 is O-GlcNAcylated at threonine 308, enhancing its stability by inhibiting TRIM21-mediated ubiquitin-dependent proteasomal degradation. O-GlcNAcylation elevated XRCC4 protein levels during DNA double-strand break damage, thereby conferring resistance to such damage. Additionally, XRCC4 Thr308 O-GlcNAcylation promotes cancer proliferation, invasion, and in vivo tumor growth. These findings suggest that downregulating O-GlcNAcylation on XRCC4 could be a potential therapeutic strategy to increase cancer sensitivity to chemotherapy or radiotherapy.