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29 January 2022 UHRF1 is indispensable for meiotic sex chromosome inactivation and interacts with the DNA damage response pathway in mice
Mengneng Xiong, Shumin Zhou, Shenglei Feng, Yiqian Gui, Jinmei Li, Yanqing Wu, Juan Dong, Shuiqiao Yuan
Author Affiliations +
Abstract

During male meiosis, the constitutively unsynapsed XY chromosomes undergo meiotic sex chromosome inactivation (MSCI), and the DNA damage response (DDR) pathway is critical for MSCI establishment. Our previous study showed that UHRF1 (ubiquitin-like, with PHD and ring finger domains 1) deletion led to meiotic arrest and male infertility; however, the underlying mechanisms of UHRF1 in the regulation of meiosis remain unclear. Here, we report that UHRF1 is required for MSCI and cooperates with the DDR pathway in male meiosis. UHRF1-deficient spermatocytes display aberrant pairing and synapsis of homologous chromosomes during the pachytene stage. In addition, UHRF1 deficiency leads to aberrant recruitment of ATR and FANCD2 on the sex chromosomes and disrupts the diffusion of ATR to the XY chromatin. Furthermore, we show that UHRF1 acts as a cofactor of BRCA1 to facilitate the recruitment of DDR factors onto sex chromosomes for MSCI establishment. Accordingly, deletion of UHRF1 leads to the failure of meiotic silencing on sex chromosomes, resulting in meiotic arrest. In addition to our previous findings, the present study reveals that UHRF1 participates in MSCI, ensuring the progression of male meiosis. This suggests a multifunctional role of UHRF1 in the male germline.

Summary Sentence

UHRF1 is directly interacts with BRCA1 and has critical role in meiotic sex chromosome inactivation (MSCI).

Graphical Abstract

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© The Author(s) 2022. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
Mengneng Xiong, Shumin Zhou, Shenglei Feng, Yiqian Gui, Jinmei Li, Yanqing Wu, Juan Dong, and Shuiqiao Yuan "UHRF1 is indispensable for meiotic sex chromosome inactivation and interacts with the DNA damage response pathway in mice," Biology of Reproduction 107(1), 168-182, (29 January 2022). https://doi.org/10.1093/biolre/ioac054
Received: 1 October 2021; Accepted: 4 March 2022; Published: 29 January 2022
JOURNAL ARTICLE
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KEYWORDS
DNA damage response
Male infertility
meiosis
meiotic sex chromosome inactivation (MSCI)
UHRF1
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