Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Genes Dev. 2020 Nov 1;34(21-22):1439-1451. doi: 10.1101/gad.343186.120. Epub 2020 Oct 15.
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.
p53 是一种强效的肿瘤抑制因子，常见于人类癌症中的突变。最近，我们证明 p53 基因在果蝇和鱼类的生殖组织中作用于限制逆转录转座子，但这种活性是否在人类体细胞中保守尚不清楚。在这里，我们表明 p53 通过协同结合 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，持续地限制人类 LINE1。与之一致的是，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 的缺失引发了与 LINE 序列相关的染色体重排，并引发了依赖 LINE1 产生的逆转录酶的炎症程序。总之，我们的观察结果表明，p53 持续在 LINE1 启动子上运作，以限制人类细胞中这些移动元件的自主拷贝。我们的研究结果进一步表明，这些逆转录元件的组成性限制可能有助于解释 p53 编码的肿瘤抑制作用，因为当 p53 缺失时，爆发的 LINE1 产生了急性致癌威胁。
