???????? ??????? ?? ????????? ????? ?????? ??? ???? ??????? ???????????? ??????, ?? ????? ????? ????????????, ?????? ????????? ??????????, ??? ???????? ?????? ??? ???????? ????????????? ??????????? ?????? ???? ????

???? ???????? ????????? ????????? ???????? ??????? ????????????? ??? ????? ???????? ????????? ???? ????, ???? ?????? ???????? ????????? ?????? ???????? ????? ??? ??? ???????? ???????????? ???? ??? ?? ???????? ??? ??? ????? ??????? ???? ???????????? ????????? ???????

?????????? ???????? ??????? ?????? ?????????, ??????????, ???????????????? ??? ??? ???????? ??????????? ???? ?????????? ?????????? ????, ?????????? ???????? ??????? ??????? ????? ?????????? ??????? ???????? ??? ??? ????????? ???????? ?? ???????? ???? ???? ???? ?????? ?????? ???? ????? ????????, ???? ????????? ????-?????? ???????? ??????? ??????, ??????? ????????, ???????????? ??? ?????????? ????????? ???????????? ?????? ???? ???? ???, ?????????? ?????? ???????? ?????????? ??? ??????????? ???? ????????

?? ???????, ???? ??????, ???? ???????????? ????? ?? ??????? / ??? ????????????? ????? ????????? ????? ??????? ?? ????? ???????? "???????? ????????? ????? ???????? ?????????????? ?? ??????? ????? ???????" ???????? ???? ?????????? ?????? ????

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

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

?? ???????? ???? ????? ?????????? ?????? ??? ??? ??????? ??????? ??? ?????????? ?????????? ??????? ????? ????? ?????????? ??? ??? ????????-???????? ??????? ???? PARP ????????????? ???????? ?????? ???????? ???? ???? ????? ???? ???????? ????

????? ????? ??? ????? ???????? ????????? ??????? ???????????? ?????? ???? ??? ???????????? ??????, ???? ????? ????????? ????? ??????? ??? ????, ???????? ??????? ???????????? ??????? ???????? ??????? ??????? ???? ????

????????-???????? ????????????? ???????????? ?????? ???? ????, ?? ???????????????? ???? ????? ??????????????????? ???????? ???? ?????????????? ???????? ????? ??????? ??? ??????? ??? ????????? ?????????? ?????? ????????-???????? ????????? ???????? ????????? ??? ????????

?????? ??????? ?? ?????? ??????? tRNA ???????? (VARS) ??????, VARS-?? ??????? ??-??????? ?????? ?????? ????? ?????? ??? ??????? ?????? ?? HDAC6 ??????? ???????? ???????, ??????????? ????????? ?????????????? (ITC) ??????? ??? ?????? ??????? ???????? ??????? Kd ≈ 2μM ?? ?????????? ?? ????????? ?????? ????? ???? ????? ??????? ??????? ?????? ??????? ???????? ????????? ???????? ??????????? ???????? ??? ?????? ???????? ???????? ??????? ??????????? ?????????? ????? ?????????? ??? ????? ??????? ??????? ????????????? ???????? ??????? ???????? ???, ?????? ??????? ?? HDAC6 ????????? ?????????? ????????? ??? ??????? ???????? ???????? ???? ??? ???????? ????????? ???????? ???? ???? ????? ???????, HDAC6 ????? ?????????, ??????? ?????????? ?????? mTOR ?????????? ???? ?????????? ?????????? ??????? ???? ??????????????? ????? ??? ??, ?? ??????? ???? ?? ?? ?????? ?????????? ???????? ??????? ??????? ????? ?? ???? ????? ????

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

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

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

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

????????, ???????? ???? ???? ?? ??????????? ????? HDAC6 ?? ???? ????? ???????? ??????? ??????? ?? ?????????? ?????? ???? ???????, ??????? ???????? ????? ???????? ??????????? ???????? ?????? ???, ?? ???????? ??????? ?????????? ????? ????????? ???????????? ?????? ??????? ????

???????, ?? ???????? ???????? ???????? ???, ?????????? ?????????? ??? ????? ?????? ???????????? ???????????? ???? ???? ?????????? ???????? ???, ??????? ??????????? ???????? ???????? ????? ????????? ???????? ??? ??? ???????? ??? ?? ????????-???????? ????? ??? PARP ?????????? ???????? ????????? ???????? ???? ???? ???? ???? ?????? ??????? ??? ???? ?????