Abstract
Accumulated evidence shows that OGT-mediated O-GlcNAcylation plays an important role in response to DNA damage repair. However, it is unclear if the “eraser” O-GlcNAcase (OGA) participates in this cellular process. Here, we examined the molecular mechanisms and biological functions of OGA in DNA damage repair, and found that OGA was recruited to the sites of DNA damage and mediated deglycosylation following DNA damage. The recruitment of OGA to DNA lesions is mediated by O-GlcNAcylation events. Moreover, we have dissected OGA using deletion mutants and found that C-terminal truncated OGA including the pseudo HAT domain was required for the recruitment of OGA to DNA lesions. Using unbiased protein affinity purification, we found that the pseudo HAT domain was associated with DNA repair factors including NONO and the Ku70/80 complex. Following DNA damage, both NONO and the Ku70/80 complex were O-GlcNAcylated by OGT. The pseudo HAT domain was required to recognize NONO and the Ku70/80 complex for their deglycosylation. Suppression of the deglycosylation prolonged the retention of NONO at DNA lesions and delayed NONO degradation on the chromatin, which impaired non-homologus end joining (NHEJ). Collectively, our study reveals that OGA-mediated deglycosylation plays a key role in DNA damage repair.
Highlights
Posttranslational modifications play key roles in DNA damage repair, in DNA double-strand break (DSB) repair [1,2,3,4]
Human OGA is a 916-residue nucleocytoplasmic protein that consists of two unique functional domains including an N-terminal catalytic domain that is responsible for the removal of O-GlcNAc, and a C-terminal pseudo–histone acetyltransferase (HAT) domain that possesses sequence homology to HAT but lacks the key residues for the binding of acetyl-coenzyme A [22,23,24,25,26]
Deglycosylation of NONO regulates its chromatin association and the non-homologus end joining (NHEJ) repair Since NONO and the Ku70/80 complex participated in DSB repair, we further explored the biological functions of these deglycosylation events in the context of DSB repair
Summary
Posttranslational modifications play key roles in DNA damage repair, in DNA double-strand break (DSB) repair [1,2,3,4]. Human OGA (hOGA) is a 916-residue nucleocytoplasmic protein that consists of two unique functional domains including an N-terminal catalytic domain that is responsible for the removal of O-GlcNAc, and a C-terminal pseudo–histone acetyltransferase (HAT) domain (residues 707–916) that possesses sequence homology to HAT but lacks the key residues for the binding of acetyl-coenzyme A (acetylCoA) [22,23,24,25,26]. These results suggest that OGA-mediated deglycosylation promotes DNA damage repair
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