Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
EMBO Rep. 2019 May;20(5). doi: 10.15252/embr.201847560. Epub 2019 Apr 4.
DNA double-strand breaks are a threat to genome integrity and cell viability. The nucleolytic processing of broken DNA ends plays a central role in dictating the repair processes that will mend these lesions. Usually, DNA end resection promotes repair by homologous recombination, whereas minimally processed ends are repaired by non-homologous end joining. Important in this process is the chromatin-binding protein 53BP1, which inhibits DNA end resection. How 53BP1 shields DNA ends from nucleases has been an enduring mystery. The recent discovery of shieldin, a four-subunit protein complex with single-stranded DNA-binding activity, illuminated a strong candidate for the ultimate effector of 53BP1-dependent end protection. Shieldin consists of REV7, a known 53BP1-pathway component, and three hitherto uncharacterized proteins: C20orf196 (SHLD1), FAM35A (SHLD2), and CTC-534A2.2 (SHLD3). Shieldin promotes many 53BP1-associated activities, such as the protection of DNA ends, non-homologous end joining, and immunoglobulin class switching. This review summarizes the identification of shieldin and the various models of shieldin action and highlights some outstanding questions requiring answers to gain a full molecular understanding of shieldin function.
DNA 双链断裂是基因组完整性和细胞活力的威胁。断裂 DNA 末端的核酶处理在决定修复这些损伤的过程中起着核心作用。通常，DNA 末端切除促进同源重组修复，而最小处理的末端通过非同源末端连接修复。在这个过程中重要的是染色质结合蛋白 53BP1，它抑制 DNA 末端切除。53BP1 如何保护 DNA 末端免受核酸酶的作用一直是一个持久的谜。最近发现的 shieldin 是一个具有单链 DNA 结合活性的四亚基蛋白复合物，为 53BP1 依赖性末端保护的最终效应子提供了一个强有力的候选物。shieldin 由 REV7 组成，REV7 是 53BP1 途径的一个已知成分，以及三个以前未被表征的蛋白质：C20orf196（SHLD1）、FAM35A（SHLD2）和 CTC-534A2.2（SHLD3）。shieldin 促进了许多 53BP1 相关的活性，如 DNA 末端的保护、非同源末端连接和免疫球蛋白类别转换。这篇综述总结了 shieldin 的鉴定以及 shieldin 作用的各种模型，并强调了一些需要回答的悬而未决的问题，以获得对 shieldin 功能的全面分子理解。
