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

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

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

?? ???????, ??????, ??????? ?????????? ????? ??? ???????? / ??? ?????????? ??????? ????????? ????? ???????? ?? "Human HDAC6 senses valine abundancy to regulate DNA damage" ?????? ?? ?????? ???? "Nature" ????????? ?????? ????????

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

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

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

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

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

???????? ?????????? ?? ??????? ?????? tRNA ???????? (VARS) ??????, deacetylase HDAC6 VARS ??????? ?? ????????? D-?????? ???????? ?????? ?????????? ???????? ????? ??????? ???????? ?? HDAC6 ???????? ???????? ???????, ??????????? ?????????? ?????????????? (ITC) ??????? ??? ??????? ??????? ??????? ???????? Kd ≈ 2μM ? ??????? ???? ?????? ?? ??????? ??????????? ???????? ??????? ?????? ?????? ??????? ????? ????? ? ???????? ???????????????? ???????? ??? ?????? ??????? ????? ????? ????????? ??????????? ????? ???????? ????? ???????? ?????? ?????? ???????? ???????? ??????? ???????? ???, ???????? ?????????? ?? HDAC6 ?????? ? ???????????? ???????? ??? ??????? ????????? ?????????? ??? ????? ???????? ???????????? ???? ???????? ??? ????, HDAC6 ?????? ???????????, ?????? ?????????? ?????? 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 ??????????????? ??????????? ????????? ???????, ??????? ?????????????? ?? ???????????? ?? ??????? ????? ?????????????? (TDG) -????????? ?????? DNA ???????????? ?????????? ????????? ???? DNA ???????-????????? ?????? ???? ???????? TET2 ChIP-Seq ?? ???-???????? ?????????? ??????????????? END-Seq ??? ddC S1 END-Seq ???? ?????? ???, ??? ???????? ??????? ?? ??????? ???? DNA ??????? ??????????? ???? ??????? ???? ?????? ??????? DNA ????? ???? ????????????????????? (5fC/5caC) ? TDG ??????? ?????? ??????? ??? ????????? ????? ???? ?????? ????

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

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

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

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