Age and insulin-like growth factor-1 impact PCNA monoubiquitination in UVB-irradiated human skin.
Age and insulin-like growth factor-1 impact PCNA monoubiquitination in UVB-irradiated human skin.
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DOI：
10.1016/j.jbc.2021.100570
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Kemp MG
中科院分区：
文献类型：
--
作者：
Hutcherson RJ;Gabbard RD;Castellanos AJ;Travers JB;Kemp MG
非黑色素瘤皮肤癌主要发生在60岁以上的人群中，其特征是角质形成细胞DNA中存在大量紫外线(UV)特征突变。尽管老年皮肤去除DNA中紫外线光产物的效率低于年轻人皮肤，但尚不清楚其他存活但潜在突变的DNA损伤耐受系统的利用是否会在老年人中发生改变，如跨病变合成(TLS)。使用复制DNA聚合酶钳夹蛋白增殖细胞核抗原的单素化作为TLS途径激活的生化标志物，我们发现65岁以上的人的皮肤受到紫外线照射后，其增殖细胞核抗原的单素化水平高于年轻人的皮肤。此外，根据先前的报道，胰岛素样生长因子-1(IGF-1)信号在老年人皮肤中UVB DNA损伤反应的改变中所起的作用，我们发现，药物抑制IGF-1受体(IGF-1R)和剥夺IGF-1都增强了UVB诱导的体外人皮肤和体外角质形成细胞中的增殖细胞核抗原的单泛素化。有趣的是，尽管TLS DNA聚合酶Pol ETA可以准确地复制紫外线诱导的DNA中的主要光产物，但我们发现在没有IGF-1R信号的情况下，它无法在染色质上积累，并且这种表型与体外角质形成细胞的诱变增加有关。因此，老年皮肤中IGF-1/IGF-1R信号的改变可能使表皮角质形成细胞在UVB暴露后进行更具诱变性的DNA合成。
Nonmelanoma skin cancers occur primarily in individuals over the age of 60 and are characterized by an abundance of ultraviolet (UV) signature mutations in keratinocyte DNA. Though geriatric skin removes UV photoproducts from DNA less efficiently than young adult skin, it is not known whether the utilization of other prosurvival but potentially mutagenic DNA damage tolerance systems such as translesion synthesis (TLS) is altered in older individuals. Using monoubiquitination of the replicative DNA polymerase clamp protein PCNA (proliferating cell nuclear antigen) as a biochemical marker of TLS pathway activation, we find that UVB exposure of the skin of individuals over the age of 65 results in a higher level of PCNA monoubiquitination than in the skin of young adults. Furthermore, based on previous reports showing a role for deficient insulin-like growth factor-1 (IGF-1) signaling in altered UVB DNA damage responses in geriatric human skin, we find that both pharmacological inhibition of the IGF-1 receptor (IGF-1R) and deprivation of IGF-1 potentiate UVB-induced PCNA monoubiquitination in both human skin ex vivo and keratinocytes in vitro. Interestingly, though the TLS DNA polymerase Pol eta can accurately replicate the major photoproducts induced in DNA by UV radiation, we find that it fails to accumulate on chromatin in the absence of IGF-1R signaling and that this phenotype is correlated with increased mutagenesis in keratinocytes in vitro. Thus, altered IGF-1/IGF-1R signaling in geriatric skin may predispose epidermal keratinocytes to carry out a more mutagenic form of DNA synthesis following UVB exposure.
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DOI：
10.1083/jcb.201008076
发表时间：
2011-01-24
期刊：
The Journal of cell biology
影响因子：
--
作者：
Göhler T;Sabbioneda S;Green CM;Lehmann AR
通讯作者：
Lehmann AR
影响因子：
16.6
作者：
Sancar, Aziz
通讯作者：
Sancar, Aziz
DOI：
10.1007/978-90-481-3471-7_10
发表时间：
2010-01-01
期刊：
GENOME STABILITY AND HUMAN DISEASES
影响因子：
--
作者：
Cruet-Hennequart, Severine;Gallagher, Kathleen;Carty, Michael P.
通讯作者：
Carty, Michael P.
影响因子：
4
作者：
Andrade-Lima, Leonardo C.;Andrade, Luciana N.;Menck, Carlos F. M.
通讯作者：
Menck, Carlos F. M.
影响因子：
5.6
作者：
BARRECA, A;DELUCA, M;MINUTO, F
通讯作者：
MINUTO, F