Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation.
Fumarate hydratase loss promotes mitotic entry in the presence of DNA damage after ionising radiation.
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在电离辐射后存在DNA损伤的情况下，富马酸水合物损失会促进有丝分裂的进入。
DOI：
10.1038/s41419-018-0912-3
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发表时间：
2018-09-06
影响因子：
9
通讯作者：
Frezza C
中科院分区：
文献类型：
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作者：
Johnson TI;Costa ASH;Ferguson AN;Frezza C
对DNA损伤的反应改变通常与基因组不稳定性有关，这是癌症的标志。富马酸水合酶（FH）最近被表征为通过富马酸的局部生产在非同源末端连接（NHEJ）中所需的DNA修复因子。FH中的失活生殖系突变导致遗传性平滑肌瘤病和肾细胞癌（HLRCC），这是一种以富马酸盐蓄积为特征的癌症综合征。最近的数据表明，在FH缺陷细胞中，富马酸盐抑制DNA双链断裂后的同源重组DNA修复，损害基因组完整性。在这里，我们表明，FH损失赋予抵抗电离辐射（IR）引起的DNA损伤，并促进早期有丝分裂进入IR后，在特定的方式，即使在未修复的损伤的存在下，通过抑制检查点维护。我们还发现，在未经处理的FH缺陷细胞中可检测到更高水平的DNA损伤灶。总体而言，这些数据表明，FH损失和富马酸盐蓄积导致G2检查点减弱，易于发生内源性DNA损伤并赋予IR抗性。
An altered response to DNA damage is commonly associated with genomic instability, a hallmark of cancer. Fumarate hydratase (FH) was recently characterised as a DNA repair factor required in non-homologous end-joining (NHEJ) through the local production of fumarate. Inactivating germline mutations in FH cause hereditary leiomyomatosis and renal cell cancer (HLRCC), a cancer syndrome characterised by accumulation of fumarate. Recent data indicate that, in FH-deficient cells, fumarate suppresses homologous recombination DNA repair upon DNA double-strand breaks, compromising genome integrity. Here, we show that FH loss confers resistance to DNA damage caused by ionising radiation (IR), and promotes early mitotic entry after IR in a fumarate-specific manner, even in the presence of unrepaired damage, by suppressing checkpoint maintenance. We also showed that higher levels of DNA damage foci are detectable in untreated FH-deficient cells. Overall, these data indicate that FH loss and fumarate accumulation lead to a weakened G2 checkpoint that predisposes to endogenous DNA damage and confers resistance to IR.
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影响因子：
9.8
作者：
Yogev O;Yogev O;Singer E;Shaulian E;Goldberg M;Fox TD;Pines O
通讯作者：
Pines O
影响因子：
16
作者：
Sivanand S;Rhoades S;Jiang Q;Lee JV;Benci J;Zhang J;Yuan S;Viney I;Zhao S;Carrer A;Bennett MJ;Minn AJ;Weljie AM;Greenberg RA;Wellen KE
通讯作者：
Wellen KE
DOI：
10.1083/jcb.201011083
发表时间：
2011-04-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Harrigan JA;Belotserkovskaya R;Coates J;Dimitrova DS;Polo SE;Bradshaw CR;Fraser P;Jackson SP
通讯作者：
Jackson SP
影响因子：
--
作者：
Yang Y;Valera VA;Padilla-Nash HM;Sourbier C;Vocke CD;Vira MA;Abu-Asab MS;Bratslavsky G;Tsokos M;Merino MJ;Pinto PA;Srinivasan R;Ried T;Neckers L;Linehan WM
通讯作者：
Linehan WM
影响因子：
64.8
作者：
通讯作者：
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