TET3 SUMOylation enhances neuronal DNA damage repair and neuroprotection after ischemic stroke

Ischemic stroke causes significant neuronal DNA damage, but the mechanisms regulating DNA repair remain unclear. This study investigates the role of Ten-eleven translocase 3 (TET3) in DNA damage repair and its potential neuroprotective effects in ischemic stroke. Here we show that the TET3 protein level was significantly increased in the peri-infarct cortex of mice with transient middle cerebral artery occlusion (tMCAO). Knockdown of the TET3 gene significantly worsened neurological deficits and increased infarct volume in tMCAO mice, while TET3 overexpression exhibited the opposite effects and significantly enhanced neuronal DNA damage repair. Mechanistically, SUMO2-specific conjugation of TET3 at lysine residues K1188 and K1397 enhanced its nuclear localization, protein stability, and neuronal 5hmC levels. Furthermore, SUMOylated TET3 effectively reduced DNA damage and improved neurological outcomes following ischemic stroke, whereas a SUMO site-deficient mutant failed to confer these protective effects. Our study reveals a novel mechanism by which SUMOylated TET3 regulates neuronal DNA damage repair in ischemic stroke, strongly suggesting that upregulating TET3 SUMOylation in neurons may provide a promising therapeutic strategy to facilitate stroke recovery.