?????? ???? ??? ???????? ?? ????? ????? ?? ?????? ??? ?? ?????? ????? ?? ??? ??? ???? ???????????, ??????? ????????????? ???????, ?????????????? ??????????????? ?? ??????? ????? ??????????? ????????????? ?? ????????? ??? ????.

????? ?????? ???? ???????? ???? ??? ????? ????? ?? ??????? ??????? ???? ????? ??. ???????, ????? ?????? ???? ?????? ???? ????? ????? ?? ???????? ???????????? ????? ????? ?????????? ????? ?? ??? ???? ?????? ?????? ??????????? ????????.

????????? ?????? ???? ??????? ??????, ??????????, ?????? ???????? ??? ?? ?????? ???? ???????????? ????? ??????? ??. ???????, ????????? ?????? ???? ????????? ???? ?????????? ?????? ????? ?????????? ??? ?? ?????? ????????? ?? ????????? ????? ???? ?? ???????? ?????? ?????. ?????????? ???? ??? ?????? ??????? ??? ???????, ????????? ?????????, ?????? ??????? ?? ??????????? ???????? ???? ?????? ??????????? ??? ????. ???? ?????, ??????? ?? ????? ???????? ?????????? ?? ??????????????? ????? ????????? ?.

2024 ????????? 20 ?? ???, ????? ????? ?????????? ?????? ?????????? / 10 ?? ??????? ???? ????? ?????? ????? ??????? "???? HDAC6 DNA ????? ??????? ????? ???? ??????? ???????? ????" ?? ??????? ??????????? ????? ?????? ????????? ??? ????.

??? ???????? ????? ?? ??????-??????? ????????? ?? ???? ??????????? HDAC6 ???????? ??? ???, ?????? ???? ????? HDAC6 ?? ????????? ???????? ???????????? ???? ??? ??????? ?????????? ???????? ?? ??? ??? ?????? TET2 ??????????????? ???? ?????? ?? DNA ???? ??? ????.

????????? ???? ???, ??? ?????? ?????????? ?????????????? ?????? ?? ???, ??????? ????????? ???????????? ???? ???? ?????????? HDAC6 ?? ??????? ?????? ???? ?????????-???????????????? (SE14) ?????????? ????? ????? ?? ??? ??? ??? ???? ??????? ???????? ????. ?????? ????????? ??????????? ??? ??, ???????? ??????? ???? ????? ?? PARP ???????? ??????? ?????? ?????? ?????? ??? ???????.

??? ??????????? ???? ????? ?????????? ????? ????? ???? DNA ????? ??????? ??? ?? ???????????? ???? ??? ???, PARP ?????? ??? ???????? ???????-???? ???? ???? ????? ??? ?????? ????????? ???? ?? ???? ???????? ????? ????.

?????? ???? ?????? ???????????? ?????? ???? ??????? ?????? ?????? ????? ???? ??? ?? ???? ?????? ???? ??????????? ???????? ???????? ???? ????????? ???????? ?? ????? ?????? ??????????????? ??? ?????? ?.

??????-????? ???????? ???????????? ????? ????? ????, ?????? ???????????? ??? ???????? ??????????????-????????????? ?????? ?????? ???? ????????????? ?????? ??????? ?????? ??? ?? ???, ??????? ??? ???????? ????? ??????-????? ???????? ?????????? ??????? ????? ???? ??? ???.

????? valyl tRNA ???????? (VARS) ??? ?????, deacetylase HDAC6, VARS ?? ???? ??? ???????? D-valine ????? ????????? ???????? ?? ?? ???????? ???? ????. ????????? ????? ?????? ??????, ?????? ???????? ?????????? (ITC) ?????? ?????? ?? ??? ??????? ?????? ?????? ???? HDAC6 ?? Kd ≈ 2μM ????????????? ???? valine ?????? ?????? ?? ???? ?? ???????? ???????? ?????? ???. ???????? ??????? ????? ???????? ?????? ?????? ??????????? ????? ????????? ????? ??? ????? ???????? ?? ?????? ???? ???????? ????? ???? ???? ?????????? ???????? ?????? ?????? ?????? ??. valine ?????????? ????? ?????? ?????? ????????? ????????, HDAC6 valine ?? ??????????? ???????? ?? ???? ???? ????? ????? ???? ?????? ??????? ????? ????? ???? ????? ???? ???? ???????? ???? ????. ?? ?????, HDAC6 knockout ?????, valine ???? ????? ????? mTOR ???? ?????? ??????? ????? ???? ???????? ??? ?????? ???? ??? ????? ???? ???, ??? ?????? ????????????? ?????? ???? ?????? ???? ??????? ??? ????? ?? ????? ????.

HDAC6 ?????? ?????? ?? ?????? ??? ?? ??????????????? ?????? ????? ????. ???????? ???????? ????? ??? HDAC6 ??????? ??? ?? ???? ????? ?????? ????? ???? HDAC6 ??? SE14 ??? ???? ?????? ?????? ??? ????. ??????? ?????? ???, ??????? ???????? ????? ???????? ???? ????? SE14 ??? ?????????? ?? HDAC6 ?? ????? ????? ????. ?????????? (?????? ?? ?????) HDAC6 ???? ???, ????? HDAC6 ?????? ??? ?????? ????. ??? ???? ????? ?????? ????????? ????? ????? ??? ???????? ???? ????, ????? ???????? ?????? ???? ??????????? ????? ??????? ?????? ??????????? ??? ??? ????.

HDAC6 ??? SE14 ??? ???? ?????? ??????? ?????? ??? ??? ?????? ?? ??????, ???????? ?????? ??? HDAC6 ?? ??????? ?? ????? ??????? ???????? ????? ??????? ???????? ????? ?? ??? ??? ???????? ?? ???????????????? ???? ???? ????. ?????? ?????? ??????? ???? ?? HDAC6 ?? ??????????????? ???? ??? ???????? SE14 ???? ?????? ??????? ?????? ????????? ??? ????????, ?????? ????? ??????? ?????? ?????????? HDAC6 ???????? ??? ?? ???? ?? ???????? ???? ????. ??????? ??????????? ????? (DAC1 ?? DAC2) DNA ????????????????????? TET2 ?? ??????????? ?????? (CD ???) ?????? ?? ???, TET2 ?? ???????????? ?????????? ????, ???? ??? ??????? ??????????????? ??????? ????. WGBS, ACE-Seq ?? MAB-Seq ???? ???????????? ??????? ????? ?????? ??????, ?????? ????? ??????? ???????? HDAC6-TET2 ???? ????? ???? ??????????? DNA ??????????? ?????????? ?? ???? ?? ??? ???????? ?????? ?????. ??? ???, ???????? ?????????????? ??????? ???? ????? ??????? DNA ????????????? (TDG) ?? ????? ??????????? DNA ??????????? ????? ?????? ?????? ?? DNA ???-???? ??????? ???? ?? ????. TET2 ChIP-Seq ???-????????? ?????????? ??????? END-Seq ?? ddC S1 END-Seq ??? ??????? ????????, ?????? ?????? DNA ????? ?????????? ??? ?? ??? ????? ?????. ?????? ????????? ????? DNA ????? ? ????????????????????? (5fC/5caC) TDG ??? ???????? ????? ??? ???? ????? ?? ??? ????.

??? ??? ??, ???????? ?? ?????? ?????? ???? ??? ???, ??? ???? ????? ???????? ?????? ???? ?????? ??????????????? ?????? ??????? ?? ?????? ??? ??????, HDAC6-TET2-TDG ???? ????? ???? ?????? DNA ????? ???????? ???? ??? ???? ?????????? ?????? ??? ???????? ???.

???? ???? ????? ?? ?????? ???? ?????????? ??????????? ?? ??????? ????? ?? ????? ?????? ????? ???? ??? ???? ??? ???? ????? ????? ?? ????????? ????? ???? ?????? ???? ???????? ??? ???? ??. ?????? ?????? DNA ???? ??? ?? ???? ?? ????????? ???, ?????? ????????????? ?????? ???? ????? ????????? ??? ??????? ???? ???????? ???????? ???????? ???. ?????????? ?????? xenograft ?????? ???????, ?????? ??????-???? ?? ???? ????? (0.41% ??????, w/w) ??? ????? ???? ???? ?????? ?????? ?????? ???? ??? ???????. ?????????? ?? ????????? ???????? ???????, ???????-???? ?? ???? ????? ?????????? ?????? PDX ???????? ?????? ?????? ?????? ???? ?? ???????? ?????? ?? ???????? ???????? ?????? ?????. ?????? ??????????, ??? ?? ?????? ?????? ???? ?? HDAC6 ????????? ????????, 5hmC ?????? ?? DNA ???? ??? ???????? ????????? ???. DNA ???? ??? ????? ?????? ???? ???????????? ?? ??????, PARP ?????? ?????? ???????? DNA ???????????? ????? ?????? ??????? ???? ?. ??????-???? ?? ???? ??? ?? PARP ?????? ????????? ??????? ?????? ???? ????? ?????? ???? ??? ???? ?????? ?? ?? ???????? ???? ??? ???, DNA ???? ??? ???????? ???????? ????????? ????? ???? ????????? ???? ?????? ?????? ?????.

????? ??????, ??????????? ???? ???? ??????????? ?? HDAC6 ??? ????????????? ?????? ????? ??????? ?? ?? ??????? ?????? ??????????? ?? ??? ?? ????? ????? ??? ??????? ???????? ???????? ???? ????, ?????? ???? ???????? ??? ??????????? ???????? ?????? ????????? ???????? ????.

??? ?????, ??? ???????? ???? ?????????? ?????, ?????????? ??????? ?? DNA ???? ????????????????? ???????? ?? ???????????? ???????? ????, ???? ??? ????????? ???? ?????????? ?????? ???????? ?????? ????, ?? ???????-???? ???? ???? ?? PARP ???????? ??????? ?????? ????????? ???? ?? ???? ???????? ??? ?????? ?? ???? ?? ???? ???.