LINP1 lncRNA expression profile is modulated in response to DNA damage

R. Carriero, Lucia Maita, S. Bione, G. Biamonti, A. Montecucco
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Abstract

Rapidly dividing cancer cells show elevated levels of DNA double-strand breaks (DSBs) resulting from replication stress and linked to genome instability. To verify the hypothesis that a low level of endogenous replicative DNA damage may impact gene expression programs and cell biology features relevant to cancer progression, we used DNA ligase I (LigI) defective 46BR.1G1 fibroblasts, deriving from a patient who died at 19 for lymphoma, and the 7A3 cell clone, obtained from 46BR.1G1 by stably expressing ectopic wild-type LigI. LigI deficiency impairs maturation of newly synthesized DNA and increases the number of DSBs and γH2AX foci, features associated with genome instability commonly found also in pre-neoplastic lesions. In order to decipher the strategy used to cope with replicative DNA damage, we have compared gene expression profiles in 46BR.1G1 and 7A3 cells. Among the differentially expressed genes, we identified a group of long noncoding RNAs (lncRNAs) which show significant transcriptional alteration in 46BR.1G1 cells, and appear to be relevant for cancer progression. An interesting up-regulated lncRNA in 46BR.1G1 cells is LINP1 (lncRNA in nonhomologous end joining (NHEJ) pathway 1) which has been shown to be involved in DNA repair. We have observed that LINP1 up-regulation contributes to proliferation and survival of 46BR.1G1 that could account for genome instability. Moreover, we observed that LINP1 is upregulated at later times in control human fibroblasts exposed to exogenous sources of DNA damage. Our observations support the notion that LINP1 lncRNA targeting could reduce the DNA repair efficacy of tumour cells. * These authors contributed equally to this work.
LINP1 lncRNA表达谱在DNA损伤的响应中被调节
快速分裂的癌细胞显示出DNA双链断裂(DSBs)水平升高,这是由复制压力和基因组不稳定引起的。为了验证低水平的内源性复制性DNA损伤可能影响与癌症进展相关的基因表达程序和细胞生物学特征的假设,我们使用了DNA连接酶I (LigI)缺陷的46BR。来自19岁死于淋巴瘤的患者的1G1成纤维细胞和来自46BR的7A3细胞克隆。稳定表达异位野生型LigI。LigI缺乏会损害新合成DNA的成熟,增加dsb和γ - h2ax位点的数量,这些特征与基因组不稳定相关,也常见于肿瘤前病变。为了破译用于应对复制性DNA损伤的策略,我们比较了46BR的基因表达谱。1G1和7A3细胞。在差异表达基因中,我们发现了一组长链非编码rna (lncRNAs),它们在46BR中表现出显著的转录改变。1G1细胞,似乎与癌症进展有关。46BR中一个有趣的上调lncRNA。1G1细胞是LINP1(非同源末端连接(NHEJ)通路1中的lncRNA),已被证明参与DNA修复。我们观察到LINP1的上调有助于46BR的增殖和存活。1G1可以解释基因组的不稳定性。此外,我们观察到,在暴露于外源DNA损伤的对照人类成纤维细胞中,LINP1在后期上调。我们的观察结果支持这样的观点,即靶向LINP1的lncRNA可能会降低肿瘤细胞的DNA修复功效。这些作者对这项工作贡献相同。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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