Identifying roles for R-loops in germline DSB repair

遗传信息的稳定遗传依赖于卵细胞和精子细胞通过减数分裂从亲本细胞获得完整的染色体。将亲本染色体分选到配子中涉及到双链DNA断裂（DSB）的程序化形成，这是在RNA:DNA杂交（r -环）等结构的背景下完成的，如果不解决这些结构可能会破坏DNA的加工。该项目将表征r环及其存在如何影响减数分裂期间DSB修复的结果。该项目还旨在通过游戏和创造性探索，让不同背景的小学生接触遗传学概念，从而提高科学素养。为此，处于不同职业阶段的科学家将与公立小学合作，为孩子们提供包括动手研究在内的暑期科学体验。此外，该项目将为遗传学领域的本科生和研究生提供研究培训机会。这项研究的重点是在配子体发生过程中扰乱遗传稳定性的过程。非典型RNA:DNA杂交结构通常在减数分裂期间形成，当这些结构无法分解时，染色体就会发生不稳定。第一个目标是确定这些r环的积累影响程序化dsb修复的机制。第二个目的是研究r环在重组过程中如何影响交叉形成。该研究将在模式生物秀丽隐杆线虫中进行，并将采用细胞生物学、遗传学和基因组学方法的结合。这项研究的结果将为调控基因组稳定性的细胞过程提供重要的见解，从而为卵子和精子细胞的完整性提供重要的见解。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Stable inheritance of genetic information across generations depends on egg and sperm cells acquiring intact chromosomes from parent cells through meiosis. Sorting parent chromosomes into gametes involves programmed formation of double strand DNA breaks (DSB), which is done in the context of structures such as RNA:DNA hybrids (R-loops) that can disrupt processing of the DNA if left unresolved. This project will characterize R-loops and how their presence affects the outcomes of DSB repair during meiosis. The project also aims to improve science literacy by exposing elementary school students of diverse backgrounds to genetics concepts using play and creative exploration. For this purpose, scientists at various career stages will partner with public elementary schools to offer children summer science experiences, including hands-on research. In addition, the project will provide research training opportunities for undergraduates and graduate students in the field of genetics. The research is focused on processes that perturb genetic stability during gametogenesis. Atypical RNA:DNA hybrid structures are normally formed during meiosis, and chromosomal instability ensues when these structures fail to disassemble. The first aim is to identify mechanisms by which accumulation of these R-loops affects repair of programmed DSBs. The second aim is to examine how R-loops affect crossover formation during recombination. The studies will be performed in the model organism Caenorhabditis elegans and will employ a combination of cell biology, genetic, and genomic approaches. The outcomes of the research will provide crucial insights into cellular processes that regulate genomic stability and, therefore, the integrity of egg and sperm cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.