The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia.
The role of the DNA damage response in zebrafish and cellular models of Diamond Blackfan anemia.
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DOI：
10.1242/dmm.015495
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发表时间：
2014-07
影响因子：
4.3
通讯作者：
Lin S
中科院分区：
文献类型：
--
作者：
Danilova N;Bibikova E;Covey TM;Nathanson D;Dimitrova E;Konto Y;Lindgren A;Glader B;Radu CG;Sakamoto KM;Lin S
核糖体生物发生涉及核糖体前RNA的加工。一些核糖体蛋白（RPs）的缺乏会损害加工过程，导致Diamond Blackfan贫血（DBA），这与贫血、先天性畸形和癌症有关。p53介导了DBA的许多特征，但p53的激活机制尚不清楚。DBA的另一个特征是腺苷脱氨酶（ADA）的上调，表明核苷酸代谢的变化。在rp缺陷的斑马鱼中，我们发现了核苷酸分解代谢和生物合成的激活，这与破坏和替换有缺陷的核糖体RNA的需要是一致的。我们还发现了脱氧核苷酸三磷酸（dNTP）合成的上调，这是对复制应激和DNA损伤的典型反应。rp缺陷斑马鱼和人造血细胞均表现出ATR/ATM-CHK1/CHK2/p53通路的激活。RP缺乏的其他特征包括dNTP池不平衡、ATP耗尽和AMPK激活。外源性核苷可以降低非dba模型培养细胞的复制应激和DNA损伤。因此，我们用外源性核苷处理rp缺陷斑马鱼胚胎，观察到p53和AMPK的激活降低，细胞凋亡减少，造血功能恢复。我们的数据表明，在DBA的细胞和斑马鱼模型中，DNA损伤反应有助于p53的激活。此外，外源性核苷对rp缺陷斑马鱼的拯救表明，核苷补充剂可能对DBA的治疗有益。
Ribosomal biogenesis involves the processing of pre-ribosomal RNA. A deficiency of some ribosomal proteins (RPs) impairs processing and causes Diamond Blackfan anemia (DBA), which is associated with anemia, congenital malformations and cancer. p53 mediates many features of DBA, but the mechanism of p53 activation remains unclear. Another hallmark of DBA is the upregulation of adenosine deaminase (ADA), indicating changes in nucleotide metabolism. In RP-deficient zebrafish, we found activation of both nucleotide catabolism and biosynthesis, which is consistent with the need to break and replace the faulty ribosomal RNA. We also found upregulation of deoxynucleotide triphosphate (dNTP) synthesis – a typical response to replication stress and DNA damage. Both RP-deficient zebrafish and human hematopoietic cells showed activation of the ATR/ATM-CHK1/CHK2/p53 pathway. Other features of RP deficiency included an imbalanced dNTP pool, ATP depletion and AMPK activation. Replication stress and DNA damage in cultured cells in non-DBA models can be decreased by exogenous nucleosides. Therefore, we treated RP-deficient zebrafish embryos with exogenous nucleosides and observed decreased activation of p53 and AMPK, reduced apoptosis, and rescue of hematopoiesis. Our data suggest that the DNA damage response contributes to p53 activation in cellular and zebrafish models of DBA. Furthermore, the rescue of RP-deficient zebrafish with exogenous nucleosides suggests that nucleoside supplements could be beneficial in the treatment of DBA.
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影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
DOI：
10.1084/jem.20121061
发表时间：
2012-11-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Austin WR;Armijo AL;Campbell DO;Singh AS;Hsieh T;Nathanson D;Herschman HR;Phelps ME;Witte ON;Czernin J;Radu CG
通讯作者：
Radu CG
影响因子：
3.9
作者：
Boria, Ilenia;Garelli, Emanuela;Gazda, Hanna T.;Aspesi, Anna;Quarello, Paola;Pavesi, Elisa;Ferrante, Daniela;Meerpohl, Joerg J.;Kartal, Mutlu;Da Costa, Lydie;Proust, Alexis;Leblanc, Thierry;Simansour, Maud;Dahl, Niklas;Froejmark, Anne-Sophie;Pospisilova, Dagmar;Cmejla, Radek;Beggs, Alan H.;Sheen, Mee R.;Landowski, Michael;Buros, Christopher M.;Clinton, Catherine M.;Dobson, Lori J.;Vlachos, Adrianna;Atsidaftos, Eva;Lipton, Jeffrey M.;Ellis, Steven R.;Ramenghi, Ugo;Dianzani, Irma
通讯作者：
Dianzani, Irma
影响因子：
6.5
作者：
Danilova N;Sakamoto KM;Lin S
通讯作者：
Lin S
影响因子：
20.3
作者：
Choesmel, Valerie;Bacqueville, Daniel;Gleizes, Pierre-Emmanuel
通讯作者：
Gleizes, Pierre-Emmanuel