Xie Feng-Yun, Zhang Xiao-Guohui, Chen Juan, Xu Xin, Li Sen, Xia Tian-Jin, Chen Lei-Ning, Yin Shen, Ou Xiang-Hong, Ma Jun-Yu
Guangzhou Municipal Key Laboratory of Metabolic Diseases and Reproductive Health, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
Reproductive Medicine Center, The Affiliated Guangdong Second Provincial General Hospital of Jinan University, Guangzhou, China.
iScience. 2024 Nov 30;27(12):111508. doi: 10.1016/j.isci.2024.111508. eCollection 2024 Dec 20.
AT-rich sequence can cause structure variants such as translocations and its instability can be accelerated by replication stresses. When human 16p11.2 or 22q11.2 recurrent copy number variant (reCNV) associated AT-rich sequence was inserted upstream promoter in yeast genome, we found that downstream transcription could promote AT-rich forming cruciform structure and mediate gross genome rearrangements. When genes were flanked with direct repeats containing AT-rich sequence, copy number loss of these genes would be stimulated. Transcription-mediated AT-rich instability can be alleviated by disrupting or and exacerbated by disrupting . Deletion of homologous recombination-associated genes can not only increase AT-rich fragility but also alter the breakpoint positions. AT-rich stability was also affected by DNA topoisomerase poisons. Our results reveal that transcription can promote AT-rich-mediated genome rearrangement, which might be helpful for understanding the mechanism of reCNV formation in humans.
富含AT的序列可导致结构变异，如易位，其不稳定性可因复制应激而加速。当与人类16p11.2或22q11.2反复拷贝数变异（reCNV）相关的富含AT的序列插入酵母基因组的启动子上游时，我们发现下游转录可促进富含AT的序列形成十字形结构并介导基因组大规模重排。当基因两侧为含有富含AT序列的直接重复序列时，这些基因的拷贝数丢失会受到刺激。转录介导的富含AT序列的不稳定性可通过破坏……或……来缓解，并通过破坏……而加剧。删除与同源重组相关的基因不仅会增加富含AT序列的脆性，还会改变断点位置。富含AT序列的稳定性也受到DNA拓扑异构酶毒物的影响。我们的结果表明，转录可促进富含AT序列介导的基因组重排，这可能有助于理解人类reCNV形成的机制。
