Loss of DNA polymerase β induces cellular senescence.
Loss of DNA polymerase β induces cellular senescence.
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DOI：
10.1002/em.22206
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发表时间：
2018-08
影响因子：
2.8
通讯作者：
Cress Cabelof D
中科院分区：
文献类型：
--
作者：
Ahmed AA;Smoczer C;Pace B;Patterson D;Cress Cabelof D
我们的目的是确定唐氏综合征患者中观察到的加速衰老和细胞过早衰老与DNA聚合酶β减少有关。我们在此报道唐氏综合征患者的原代成纤维细胞显示出更强的SA-β-gal染色（增加4倍，p<0.001），p16转录丰度增加（增加3倍，p<0.01），HMGB 1核定位减少（降低1.5倍，p<0.01）。我们还发现唐氏综合征原代成纤维细胞中DNA聚合酶β的表达显著降低（下降53%，p<0.01）。为了评估DNA聚合酶β是否可能是衰老诱导的原因，我们评估了小鼠DNA聚合酶β缺失对衰老的影响。我们发现，与野生型相比，未暴露的DNA聚合酶β无效原代成纤维细胞表现出衰老细胞数量的稳健增加（11倍，p< 0.001），表明DNA聚合酶β的缺失足以诱导衰老。我们还观察到对羟基脲的响应的额外增加（比WT-HU大3倍，p<0.05）。这些数据表明，DNA聚合酶β的损失足以诱导衰老。此外，我们报告了在DNA聚合酶β无效MEFs中自发DNA双链断裂的显著诱导（比野生型增加5倍，p< 0.0001）。我们的研究结果强烈表明，DNA聚合酶β是衰老诱导的原因，合理地指出DNA聚合酶β是唐氏综合征中驱动早衰的可能因素。
We aim to establish that accelerated aging and premature cellular senescence seen in individuals with Down syndrome is related to reduced DNA polymeraseβ. We report here that primary fibroblasts from Down syndrome individuals exhibit greater SA-β-gal staining (4-fold increase, p<0.001), increased p16 transcript abundance (3-fold increase, p<0.01), and reduced HMGB1 nuclear localization (1.5-fold lower, p<0.01). We also find that DNA polymerase β expression is significantly reduced in Down syndrome primary fibroblasts (53% decline, p<0.01). To evaluate whether DNA polymerase β might be causative in senescence induction, we evaluated the impact of murine DNA polymerase β nullizygosity on senescence. We find that unexposed DNA polymerase β -null primary fibroblasts exhibit a robust increase in the number of senescent cells compared to wild-type (11-fold, p< 0.001), demonstrating that loss DNA polymerase β is sufficient to induce senescence. We also see an additional increase in response to hydroxyurea (3-fold greater than WT-HU, p<0.05). These data demonstrate that loss of DNA polymerase β is sufficient to induce senescence. Additionally, we report a significant induction in spontaneous DNA double strand breaks in DNA polymerase β null MEFs (5-fold increase from wild-type, p< 0.0001). Our findings strongly suggest that DNA polymerase β is causative in senescence induction, reasonably pointing to DNA polymerase β as a likely factor driving the premature senescence in Down syndrome.
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影响因子：
20.3
作者：
Cabelof, Diane C.;Patel, Hiral V.;Taub, Jeffrey W.
通讯作者：
Taub, Jeffrey W.
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
3.9
作者：
Kisby, Glen E.;Kohama, Steven G.;Kow, Yoke W.
通讯作者：
Kow, Yoke W.
DOI：
10.1016/s0074-7750(10)39004-5
发表时间：
2010-01-01
期刊：
INTERNATIONAL REVIEW OF RESEARCH IN MENTAL RETARDATION, VOL 39: HEALTH ISSUES AMONG PERSONS WITH DOWN SYNDROME
影响因子：
--
作者：
Esbensen, Anna J.
通讯作者：
Esbensen, Anna J.
影响因子：
--
作者：
Hill, DA;Gridley, G;Fraumeni, JF
通讯作者：
Fraumeni, JF