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

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

SUBMITTER: Ko JY 

PROVIDER: S-EPMC12789502 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature