Monoubiquitinated Fanconi anemia D2 (FANCD2-Ub) is required for BCR-ABL1 kinase-induced leukemogenesis.
Monoubiquitinated Fanconi anemia D2 (FANCD2-Ub) is required for BCR-ABL1 kinase-induced leukemogenesis.
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DOI：
10.1038/leu.2011.91
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发表时间：
2011-08
期刊：
影响因子：
11.4
通讯作者：
Skorski, T.
中科院分区：
文献类型：
--
作者：
Koptyra, M.;Stoklosa, T.;Hoser, G.;Glodkowska-Mrowka, E.;Seferynska, I.;Klejman, A.;Blasiak, J.;Skorski, T.
Fanconi D2(FANCD2)是K561(FANCD2-Ub)上的单核苷酸，响应DNA双链断裂(DSB)刺激这些潜在致命DNA损伤的修复。FANCD2-Ub在CD34+慢性髓系白血病(CML)细胞和BCR-ABL1激酶阳性细胞系中表达上调，以响应活性氧(ROS)和DNA交联剂丝裂霉素C水平的升高。下调FANCD2和抑制FANCD2-Ub可降低CD34+CML细胞的克隆形成能力，延迟小鼠BCR-ABL1白血病的发生。Bcr-abl1阳性的FANCD2−/−白血病细胞增殖受阻可通过FANCD2的表达得到挽救。与bcr-abl1阳性的FANCD2+/+细胞相比，bcr-abl1阳性的FANCD2−/−细胞积累了更多的ROS诱导的DSB。抗氧化剂减少DSB的数量，促进bcr-abl1阳性的FANCD2−/−细胞的增殖。野生型FANCD2和FANCD2(S222A)磷酸化缺陷突变体(缺乏刺激S期检查点，但擅长DSB修复)表达，而FANCD2(K561R)单核苷酸缺陷突变体(熟练刺激S期检查点，但缺乏DSB修复)表达，减少DSB数量，促进bcr-abl1阳性FANCD2−/−细胞的增殖。我们推测FANCD2-Ub在BCR-ABL1白血病的发生中起重要作用，因为它能够促进ROS诱导的DSB的修复。
Fanconi D2 (FANCD2) is monoubiquitinated on K561 (FANCD2-Ub) in response to DNA double-strand breaks (DSBs) to stimulate repair of these potentially lethal DNA lesions. FANCD2-Ub was upregulated in CD34+ chronic myeloid leukemia (CML) cells and in BCR-ABL1 kinase –positive cell lines in response to elevated levels of reactive oxygen species (ROS) and DNA cross-linking agent mitomycin C. Downregulation of FANCD2 and inhibition of FANCD2-Ub reduced the clonogenic potential of CD34+ CML cells and delayed BCR-ABL1 leukemogenesis in mice. Retarded proliferation of BCR-ABL1 -positive FANCD2−/− leukemia cells could be rescued by FANCD2 expression. BCR-ABL1 –positive FANCD2−/− cells accumulated more ROS-induced DSBs in comparison to BCR-ABL1 –positive FANCD2+/+ cells. Antioxidants diminished the number of DSBs and enhanced proliferation of BCR-ABL1 –positive FANCD2−/− cells. Expression of wild-type FANCD2 and FANCD2(S222A) phosphorylation-defective mutant (deficient in stimulation of intra-S phase checkpoint but proficient in DSB repair), but not FANCD2(K561R) monoubiquitination-defective mutant (proficient in stimulation of intra-S phase checkpoint but deficient in DSB repair) reduced the number of DSBs and facilitated proliferation of BCR-ABL1 –positive FANCD2−/− cells. We hypothesize that FANCD2-Ub plays an important role in BCR-ABL1 leukemogenesis due to its ability to facilitate the repair of numerous ROS-induced DSBs.
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影响因子：
50.3
作者：
Klemm L;Duy C;Iacobucci I;Kuchen S;von Levetzow G;Feldhahn N;Henke N;Li Z;Hoffmann TK;Kim YM;Hofmann WK;Jumaa H;Groffen J;Heisterkamp N;Martinelli G;Lieber MR;Casellas R;Müschen M
通讯作者：
Müschen M
影响因子：
20.3
作者：
Kutler, DI;Singh, B;Auerbach, AD
通讯作者：
Auerbach, AD
影响因子：
3.9
作者：
Majsterek, I;Blasiak, J;Skórski, T
通讯作者：
Skórski, T
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
16
作者：
Garcia-Higuera, I;Taniguchi, T;D'Andrea, AD
通讯作者：
D'Andrea, AD