Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.
Genotoxic aldehyde stress prematurely ages hematopoietic stem cells in a p53-driven manner.
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遗传毒性醛应激以p53驱动的方式使造血干细胞过早老化。
DOI：
10.1016/j.molcel.2023.05.035
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发表时间：
2023-07-20
期刊：
影响因子：
16
通讯作者：
Patel KJ
中科院分区：
文献类型：
--
作者：
Wang M;Brandt LTL;Wang X;Russell H;Mitchell E;Kamimae-Lanning AN;Brown JM;Dingler FA;Garaycoechea JI;Isobe T;Kinston SJ;Gu M;Vassiliou GS;Wilson NK;Göttgens B;Patel KJ
老化的造血干细胞（HSC）显示自我更新减少和髓样分化偏好。然而，支撑这一根本转变的驱动因素和机制尚不清楚。HSC产生遗传毒性甲醛，需要解毒酶ALDH 2和ADH 5以及范可尼贫血（FA）DNA修复途径的保护。我们发现，年轻Aldh 2 −/− Fancd 2 −/−小鼠的HSC具有与老年野生型HSC相当的转录组学特征，沿着表观遗传年龄增加、端粒磨损和通过单次HSC移植量化的髓样偏向分化。此外，p53反应在Aldh 2 −/− Fancd 2 −/− HSC中被强烈激活，而p53缺失挽救了这种老化的HSC表型。为了进一步确定髓样分化偏向的起源，我们使用GFP基因报告基因来发现Vwf+髓样和巨核细胞谱系偏向的HSC的显著富集。这些结果表明，代谢衍生的甲醛-DNA损伤刺激HSC中的p53反应，以驱动加速老化。
Aged hematopoietic stem cells (HSCs) display diminished self-renewal and a myeloid differentiation bias. However, the drivers and mechanisms that underpin this fundamental switch are not understood. HSCs produce genotoxic formaldehyde that requires protection by the detoxification enzymes ALDH2 and ADH5 and the Fanconi anemia (FA) DNA repair pathway. We find that the HSCs in young Aldh2−/− Fancd2 −/− mice harbor a transcriptomic signature equivalent to aged wild-type HSCs, along with increased epigenetic age, telomere attrition, and myeloid-biased differentiation quantified by single HSC transplantation. In addition, the p53 response is vigorously activated in Aldh2 −/− Fancd2 −/− HSCs, while p53 deletion rescued this aged HSC phenotype. To further define the origins of the myeloid differentiation bias, we use a GFP genetic reporter to find a striking enrichment of Vwf+ myeloid and megakaryocyte-lineage-biased HSCs. These results indicate that metabolism-derived formaldehyde-DNA damage stimulates the p53 response in HSCs to drive accelerated aging.
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DOI：
10.1056/nejmoa1409405
发表时间：
2014-12-25
期刊：
The New England journal of medicine
影响因子：
--
作者：
Genovese G;Kähler AK;Handsaker RE;Lindberg J;Rose SA;Bakhoum SF;Chambert K;Mick E;Neale BM;Fromer M;Purcell SM;Svantesson O;Landén M;Höglund M;Lehmann S;Gabriel SB;Moran JL;Lander ES;Sullivan PF;Sklar P;Grönberg H;Hultman CM;McCarroll SA
通讯作者：
McCarroll SA
在健康个体中预测急性髓样白血病的风险。
影响因子：
64.8
作者：
Abelson S;Collord G;Ng SWK;Weissbrod O;Mendelson Cohen N;Niemeyer E;Barda N;Zuzarte PC;Heisler L;Sundaravadanam Y;Luben R;Hayat S;Wang TT;Zhao Z;Cirlan I;Pugh TJ;Soave D;Ng K;Latimer C;Hardy C;Raine K;Jones D;Hoult D;Britten A;McPherson JD;Johansson M;Mbabaali F;Eagles J;Miller JK;Pasternack D;Timms L;Krzyzanowski P;Awadalla P;Costa R;Segal E;Bratman SV;Beer P;Behjati S;Martincorena I;Wang JCY;Bowles KM;Quirós JR;Karakatsani A;La Vecchia C;Trichopoulou A;Salamanca-Fernández E;Huerta JM;Barricarte A;Travis RC;Tumino R;Masala G;Boeing H;Panico S;Kaaks R;Krämer A;Sieri S;Riboli E;Vineis P;Foll M;McKay J;Polidoro S;Sala N;Khaw KT;Vermeulen R;Campbell PJ;Papaemmanuil E;Minden MD;Tanay A;Balicer RD;Wareham NJ;Gerstung M;Dick JE;Brennan P;Vassiliou GS;Shlush LI
通讯作者：
Shlush LI
端粒：一种倍性 - 敏锐的方法，用于从整个基因组测序数据中估算端粒长度。
影响因子：
4.6
作者：
Farmery JHR;Smith ML;NIHR BioResource - Rare Diseases;Lynch AG
通讯作者：
Lynch AG
DOI：
10.1038/nrg3246
发表时间：
2012-10
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A