p53 is a potent tumor suppressor and commonly mutated in human cancers. Recently, we demonstrated that p53 genes act to restrict retrotransposons in germline tissues of flies and fish but whether this activity is conserved in somatic human cells is not known. Here we show that p53 constitutively restrains human LINE1s by cooperatively engaging sites in the 5′UTR and stimulating local deposition of repressive histone marks at these transposons. Consistent with this, the elimination of p53 or the removal of corresponding binding sites in LINE1s, prompted these retroelements to become hyperactive. Concurrently, p53 loss instigated chromosomal rearrangements linked to LINE sequences and also provoked inflammatory programs that were dependent on reverse transcriptase produced from LINE1s. Taken together, our observations establish that p53 continuously operates at the LINE1 promoter to restrict autonomous copies of these mobile elements in human cells. Our results further suggest that constitutive restriction of these retroelements may help to explain tumor suppression encoded by p53, since erupting LINE1s produced acute oncogenic threats when p53 was absent.

中文翻译：

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p53 直接抑制人类 LINE1 转座子

p53 是一种有效的肿瘤抑制因子，通常在人类癌症中发生突变。最近，我们证明 p53 基因在果蝇和鱼的种系组织中起到限制反转录转座子的作用，但这种活性是否在人体细胞中是保守的尚不清楚。在这里，我们表明 p53 通过合作参与 5'UTR 中的位点并刺激这些转座子上抑制性组蛋白标记的局部沉积来组成性地抑制人类 LINE1。与此一致，p53 的消除或 LINE1 中相应结合位点的去除促使这些逆转录元件变得过度活跃。同时，p53 缺失会引发与 LINE 序列相关的染色体重排，还会引发依赖于 LINE1 产生的逆转录酶的炎症程序。综合起来，我们的观察表明，p53 在 LINE1 启动子上持续运行，以限制人类细胞中这些移动元素的自主复制。我们的结果进一步表明，这些逆转录元件的组成性限制可能有助于解释 p53 编码的肿瘤抑制，因为当 p53 不存在时，爆发的 LINE1 会产生急性致癌威胁。