NKAPL facilitates transcription pause-release and bridges elongation to initiation during meiosis exit

Zhenlong Kang, Chen Xu, Shuai Lu, Jie Gong, Ruoyu Yan, Gan Luo, Yuanyuan Wang, Qing He, Yifei Wu, Yitong Yan, Baomei Qian, Shenglin Han, Zhiwen Bu, Jinwen Zhang, Xian Xia, Liang Chen, Zhibin Hu, Mingyan Lin (), Zheng Sun (), Yayun Gu () and Lan Ye ()
Additional contact information
Zhenlong Kang: Nanjing Medical University
Chen Xu: Nanjing Medical University
Shuai Lu: Nanjing Medical University
Jie Gong: Nanjing Medical University
Ruoyu Yan: Nanjing Medical University
Gan Luo: Nanjing Medical University
Yuanyuan Wang: Nanjing Medical University
Qing He: Nanjing Medical University
Yifei Wu: Nanjing Medical University
Yitong Yan: Nanjing Medical University
Baomei Qian: University of Science and Technology of China
Shenglin Han: Nanjing Medical University
Zhiwen Bu: Nanjing Medical University
Jinwen Zhang: Nanjing Medical University
Xian Xia: Nanjing Medical University
Liang Chen: Wuhan University
Zhibin Hu: Nanjing Medical University
Mingyan Lin: Nanjing Medical University
Zheng Sun: Baylor College of Medicine
Yayun Gu: Nanjing Medical University
Lan Ye: Nanjing Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Transcription elongation, especially RNA polymerase II (Pol II) pause-release, is less studied than transcription initiation in regulating gene expression during meiosis. It is also unclear how transcription elongation interplays with transcription initiation. Here, we show that depletion of NKAPL, a testis-specific protein distantly related to RNA splicing factors, causes male infertility in mice by blocking the meiotic exit and downregulating haploid genes. NKAPL binds to promoter-associated nascent transcripts and co-localizes with DNA-RNA hybrid R-loop structures at GAA-rich loci to enhance R-loop formation and facilitate Pol II pause-release. NKAPL depletion prolongs Pol II pauses and stalls the SOX30/HDAC3 transcription initiation complex on the chromatin. Genetic variants in NKAPL are associated with azoospermia in humans, while mice carrying an NKAPL frameshift mutation (M349fs) show defective meiotic exit and transcriptomic changes similar to NKAPL depletion. These findings identify NKAPL as an R-loop-recognizing factor that regulates transcription elongation, which coordinates the meiotic-to-postmeiotic transcriptome switch in alliance with the SOX30/HDAC3-mediated transcription initiation.

Date: 2025
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DOI: 10.1038/s41467-024-55579-y

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