Department of Biology, School of Medicine, University of Patras, Patras, Greece.
Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
EMBO Rep. 2022 Aug 3;23(8):e54483. doi: 10.15252/embr.202154483. Epub 2022 Jun 27.
DNA lesions occur across the genome and constitute a threat to cell viability; however, damage at specific genomic loci has a relatively greater impact on overall genome stability. The ribosomal RNA gene repeats (rDNA) are emerging fragile sites. Recent progress in understanding how the rDNA damage response is organized has highlighted a key role of adaptor proteins. Here, we show that the scaffold tumor suppressor RASSF1A is recruited to rDNA breaks. RASSF1A recruitment to double-strand breaks is mediated by 53BP1 and depends on RASSF1A phosphorylation at Serine 131 by ATM kinase. Employing targeted rDNA damage, we uncover that RASSF1A recruitment promotes local ATM signaling. RASSF1A silencing, a common epigenetic event during malignant transformation, results in persistent breaks, rDNA copy number alterations and decreased cell viability. Overall, we identify a novel role for RASSF1A at rDNA break sites, provide mechanistic insight into how the DNA damage response is organized in a chromatin context, and provide further evidence for how silencing of the RASSF1A tumor suppressor contributes to genome instability.
DNA 损伤发生在整个基因组中，对细胞存活构成威胁；然而，特定基因组位置的损伤对整体基因组稳定性的影响相对更大。核糖体 RNA 基因重复（rDNA）是新兴的脆弱位点。最近在理解 rDNA 损伤反应如何组织方面的进展强调了衔接蛋白的关键作用。在这里，我们表明支架肿瘤抑制因子 RASSF1A 被招募到 rDNA 断裂处。RASSF1A 通过 53BP1 被招募到双链断裂处，并且依赖于 ATM 激酶对丝氨酸 131 的 RASSF1A 磷酸化。通过靶向 rDNA 损伤，我们揭示了 RASSF1A 募集促进局部 ATM 信号转导。RASSF1A 沉默是恶性转化过程中的一种常见表观遗传事件，导致持续的断裂、rDNA 拷贝数改变和细胞活力下降。总的来说，我们在 rDNA 断裂部位确定了 RASSF1A 的新作用，为在染色质背景下如何组织 DNA 损伤反应提供了机制见解，并进一步证明了 RASSF1A 肿瘤抑制因子的沉默如何导致基因组不稳定。
