The role of Tudor family proteins in piRNA biogenesis and genome defense.

Tudor 家族蛋白在 piRNA 生物发生和基因组防御中的作用。

• 批准号: 310347643
• 负责人: Professorin Dr. Teresa Carlomagno
• 金额: --
• 依托单位: School of Biosciences
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/310347643?language=en
• 关键词: role; Tudor; family; proteins; piRNA

piRNAs form a recently discovered class of non-coding RNAs that protect the germline genome of animals from the activity of resident transposons. They prevent genome instability and ensure faithful information transfer to the next generation. Lately, piRNA were also found in somatic cells, suggesting their role in gene expression regulation and were implicated in various diseases including infertility and cancer. However, the mechanism of production and action of piRNAs is still largely ambiguous, preventing their applications in biotechnology or medicine. Recent genomic screens have identified Tudor domain containing proteins as particularly abundant players in the piRNA pathway. By interacting with PIWIs and helicases they could mediate the assembly of various macromolecular complexes and play a central coordinating role. Only few Tudor-containing proteins have been studied in detail to date, and their diversity, specificity and molecular function remains elusive. Here, we embark in characterizing a critical Tudor-containing piRNA biogenesis factors, Qin/Kumo, using an integrated biochemistry, structural biology, and cell biology approach. We aim to understand: i) how Tudors recognize several partner proteins specifically; ii) how various Tudor domains interact and communicate with other domains; iii) how they coordinate the action of piRNA factors; iv) and what is their exact role in piRNA biogenesis. Our results will provide key insights into the still mysterious process of piRNA biogenesis, and establish general principles of Tudor function. Ultimately, this will enable the rational design of antagonists to interfere with the piRNA pathway, opening new avenues towards applications of the pathway for studying disease mechanisms, improving transposon-based genetic engineering, and even for medicine.

piRNA形成最近发现的一类非编码RNA，其保护动物的生殖系基因组免受常驻转座子的活性。它们可以防止基因组不稳定，并确保信息忠实地传递给下一代。最近，在体细胞中也发现了皮尔纳，表明它们在基因表达调控中的作用，并与包括不育和癌症在内的各种疾病有关。然而，piRNA的产生和作用机制在很大程度上仍然是模糊的，阻碍了它们在生物技术或医学中的应用。最近的基因组筛选已经将含有Tudor结构域的蛋白质鉴定为皮尔纳途径中特别丰富的参与者。通过与PIWI和解旋酶的相互作用，它们可以介导各种大分子复合物的组装，并发挥中心配位作用。迄今为止，只有很少的Tudor蛋白被详细研究，它们的多样性，特异性和分子功能仍然难以捉摸。在这里，我们开始使用综合生物化学，结构生物学和细胞生物学方法来表征关键的Tudor含皮尔纳生物发生因子Qin/Kumo。我们的目标是了解：i）Tudor如何特异性识别几种伴侣蛋白; ii）各种Tudor结构域如何与其他结构域相互作用和通信; iii）它们如何协调皮尔纳因子的作用; iv）它们在皮尔纳生物发生中的确切作用。我们的研究结果将为皮尔纳生物发生的神秘过程提供关键见解，并建立Tudor功能的一般原则。最终，这将使拮抗剂的合理设计能够干扰皮尔纳途径，为研究疾病机制，改善基于转座子的基因工程甚至医学的途径的应用开辟新的途径。