Identifying roles for R-loops in germline DSB repair

确定 R 环在种系 DSB 修复中的作用

• 批准号: 2027955
• 负责人: Sarit Smolikove
• 金额: $ 75万
• 依托单位: University of Iowa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2027955&HistoricalAwards=false
• 关键词: Identifying; roles; loops; germline; DSB

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.

遗传信息的跨代稳定遗传取决于卵细胞和精细胞通过减数分裂从母细胞获得完整的染色体。将亲本染色体分选到配子中涉及双链DNA断裂（DSB）的程序化形成，这是在诸如RNA：DNA杂交体（R环）的结构的背景下完成的，如果不解决，则可以破坏DNA的加工。该项目将表征R环以及它们的存在如何影响减数分裂期间DSB修复的结果。该项目还旨在通过让不同背景的小学生接触遗传学概念，利用游戏和创造性探索来提高科学素养。为此，处于不同职业阶段的科学家将与公立小学合作，为儿童提供暑期科学体验，包括动手研究。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发生过程中扰乱遗传稳定性的过程。非典型的RNA：DNA杂交结构通常在减数分裂过程中形成，当这些结构不能分解时，染色体不稳定性随之而来。第一个目的是确定这些R环的积累影响程序DSB修复的机制。第二个目的是研究R环如何影响重组过程中的交叉形成。这些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，遗传学和基因组方法的组合。该研究成果将为调节基因组稳定性的细胞过程提供重要见解，从而确保卵细胞和精子细胞的完整性。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

R-loop-induced irreparable DNA damage evades checkpoint detection in the C. elegans germline.

• DOI: 10.1093/nar/gkac621
• 发表时间: 2022-08-12
• 期刊: NUCLEIC ACIDS RESEARCH
• 影响因子: 14.9
• 作者: Hicks, Tara;Koury, Emily;McCabe, Caleb;Williams, Cameron;Crahan, Caroline;Smolikove, Sarit
• 通讯作者: Smolikove, Sarit

Continuous double-strand break induction and their differential processing sustain chiasma formation during Caenorhabditis elegans meiosis

• DOI: 10.1016/j.celrep.2022.111403
• 发表时间: 2022-09-27
• 期刊: CELL REPORTS
• 影响因子: 8.8
• 作者: Hicks，Tara;Trivedi，Shalini;Silva，Nicola
• 通讯作者: Silva，Nicola