The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants.
The interaction between ALKBH2 DNA repair enzyme and PCNA is direct, mediated by the hydrophobic pocket of PCNA and perturbed in naturally-occurring ALKBH2 variants.
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DOI：
10.1016/j.dnarep.2015.09.008
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发表时间：
2015-11
期刊：
影响因子：
3.8
通讯作者：
van Loon, Barbara
中科院分区：
文献类型：
--
作者：
Fu, Dragony;Samson, Leona D.;Huebscher, Ullrich;van Loon, Barbara
人类AlkB同系物2（ALKBH 2）是一种DNA修复酶，通过氧化去甲基化催化DNA甲基化损伤的直接逆转。虽然ALKBH 2与增殖细胞核抗原（PCNA）在DNA复制灶中共定位，但这两种蛋白质是否单独形成复合物或需要其他组分相互作用仍不清楚。在这里，我们证明了ALKBH 2可以直接与PCNA相互作用，独立于其他细胞因子，我们确定了介导这种相互作用的关键结构域的PCNA的疏水口袋。此外，我们发现PCNA与ALKBH 2的关联在DNA复制过程中显著增加，表明ALKBH 2与PCNA形成细胞周期依赖性复合物。有趣的是，我们发现ALKBH 2种系变异体以及在癌症中发现的变异体显示与PCNA的相互作用改变。我们的研究揭示了PCNA的ALKBH 2结合界面，并表明种系和体细胞ALKBH 2变体都可能对DNA修复中的ALKBH 2功能产生细胞效应。
Human AlkB homolog 2 (ALKBH2) is a DNA repair enzyme that catalyzes the direct reversal of DNA methylation damage through oxidative demethylation. While ALKBH2 colocalizes with proliferating cell nuclear antigen (PCNA) in DNA replication foci, it remains unknown whether these two proteins alone form a complex or require additional components for interaction. Here, we demonstrate that ALKBH2 can directly interact with PCNA independent from other cellular factors, and we identify the hydrophobic pocket of PCNA as the key domain mediating this interaction. Moreover, we find that PCNA association with ALKBH2 increases significantly during DNA replication, suggesting that ALKBH2 forms a cell-cycle dependent complex with PCNA. Intriguingly, we show that an ALKBH2 germline variant, as well as a variant found in cancer, display altered interaction with PCNA. Our studies reveal the ALKBH2 binding interface of PCNA and indicate that both germline and somatic ALKBH2 variants could have cellular effects on ALKBH2 function in DNA repair.
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影响因子：
3.8
作者：
Fu, Dragony;Samson, Leona D.
通讯作者：
Samson, Leona D.
影响因子：
3.8
作者：
Nay, Stephanie L.;Lee, Dong-Hyun;Bates, Steven E.;O'Connor, Timothy R.
通讯作者：
O'Connor, Timothy R.
影响因子：
3.7
作者：
Müller R;Misund K;Holien T;Bachke S;Gilljam KM;Våtsveen TK;Rø TB;Bellacchio E;Sundan A;Otterlei M
通讯作者：
Otterlei M
影响因子：
5.3
作者：
Niculescu, AB;Chen, XB;Reed, SI
通讯作者：
Reed, SI
影响因子：
14.9
作者：
Cunningham F;Amode MR;Barrell D;Beal K;Billis K;Brent S;Carvalho-Silva D;Clapham P;Coates G;Fitzgerald S;Gil L;Girón CG;Gordon L;Hourlier T;Hunt SE;Janacek SH;Johnson N;Juettemann T;Kähäri AK;Keenan S;Martin FJ;Maurel T;McLaren W;Murphy DN;Nag R;Overduin B;Parker A;Patricio M;Perry E;Pignatelli M;Riat HS;Sheppard D;Taylor K;Thormann A;Vullo A;Wilder SP;Zadissa A;Aken BL;Birney E;Harrow J;Kinsella R;Muffato M;Ruffier M;Searle SM;Spudich G;Trevanion SJ;Yates A;Zerbino DR;Flicek P
通讯作者：
Flicek P