U2OS shE4F1 transcriptome

Zinc finger (ZnF) proteins represent one of the largest families of human proteins, although most remain uncharacterized. Given that numerous ZnF proteins are able to interact with DNA and poly(ADP-ribose), there is a growing interest in the understanding of their mechanism of action in the maintenance of genome integrity. We now report that the ZnF protein E4F1 is an actor of DNA repair. Indeed, E4F1 is rapidly recruited, in a PARP-dependent manner, to DNA breaks and promotes ATR/CHK1 signaling, DNA-end resection and subsequent homologous recombination. Moreover, we identified E4F1 as a new regulator of the ATP-dependent chromatin remodeling SWI/SNF complex in DNA repair. E4F1 binds to the catalytic subunit BRG1/SMARCA4, and together with PARP-1, mediates its recruitment to DNA lesions. We also report that a proportion of human breast cancers show amplification and overexpression of E4F1 or BRG1 that are mutually exclusive with BRCA1/2 alterations. Together, these results reveal a novel function of E4F1 in the DNA damage response that orchestrates proper signaling and repair of double strand breaks and document a molecular mechanism for its essential role in maintaining genome integrity and cell survival.

锌指（Zinc finger, ZnF）蛋白是人类最大的蛋白家族之一，不过其中绝大多数仍未被充分解析。鉴于众多ZnF蛋白能够与DNA及多聚ADP核糖结合，学界对其在维持基因组完整性过程中的作用机制的研究热情日益高涨。本研究现报道，锌指蛋白E4F1是DNA修复过程中的关键因子。具体而言，E4F1可通过聚ADP核糖聚合酶（PARP）依赖的方式被快速招募至DNA断裂位点，并激活ATR/CHK1信号通路、介导DNA末端切除及后续的同源重组过程。此外，本研究还鉴定出E4F1是ATP依赖型染色质重塑SWI/SNF复合物的新型调控因子。E4F1可结合其催化亚基BRG1/SMARCA4，并与聚ADP核糖聚合酶1（PARP-1）协同，介导后者招募至DNA损伤位点。本研究同时发现，部分人类乳腺癌样本中存在E4F1或BRG1的基因扩增与过表达，且该改变与BRCA1/2的突变呈互斥关系。综上，本研究揭示了E4F1在DNA损伤应答中的全新功能——其可协调双链断裂的信号传导与修复过程，并阐明了其在维持基因组完整性与细胞存活过程中发挥核心作用的分子机制。