The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.
The R882H DNMT3A mutation associated with AML dominantly inhibits wild-type DNMT3A by blocking its ability to form active tetramers.
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DOI：
10.1016/j.ccr.2014.02.010
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发表时间：
2014-04-14
期刊：
影响因子：
50.3
通讯作者：
Ley TJ
中科院分区：
文献类型：
--
作者：
Russler-Germain DA;Spencer DH;Young MA;Lamprecht TL;Miller CA;Fulton R;Meyer MR;Erdmann-Gilmore P;Townsend RR;Wilson RK;Ley TJ
在30%的正常核型急性髓系白血病(AML)患者中，发现编码从头DNA甲基转移酶的DNMT3A的体细胞突变。大多数突变是杂合的，并在催化域(最常见的是R882H)内改变R882，这表明有可能产生显性的负面后果。与WT酶相比，R882H DNMT3A的甲基转移酶活性降低了约80%。在体外，WT和R882H DNMT3A的混合不会影响WT的活性，但这两种蛋白在细胞中的共同表达通过破坏WT酶的同源异构化能力而深刻地抑制WT酶。具有R882H突变的AML细胞在整个AML细胞基因组中都严重降低了从头甲基转移酶的活性和特定CPGS的局灶性低甲基化。
Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ~30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ~80% compared to the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity but co-expression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.
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影响因子：
5.6
作者：
Gowher, H;Loutchanwoot, P;Jeltsch, A
通讯作者：
Jeltsch, A
DOI：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
14.9
作者：
Forbes SA;Bindal N;Bamford S;Cole C;Kok CY;Beare D;Jia M;Shepherd R;Leung K;Menzies A;Teague JW;Campbell PJ;Stratton MR;Futreal PA
通讯作者：
Futreal PA
影响因子：
4.8
作者：
Kareta, Michael S.;Botello, Zaida M.;Chedin, Frederic
通讯作者：
Chedin, Frederic
影响因子：
4.8
作者：
Holz-Schietinger, Celeste;Matje, Douglas M.;Reich, Norbert O.
通讯作者：
Reich, Norbert O.