Defective Homologous Recombination Repair By Up-Regulating Lnc-HZ10/Ahr Loop in Human Trophoblast Cells Induced Miscarriage
© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH..
Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc-HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc-HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc-HZ10 transcription. Meanwhile, lnc-HZ10 also increases AhR levels by suppressing its CUL4B-mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc-HZ10 (mainly 1-447 nt) interacts with γ-H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc-HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:11 |
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| Enthalten in: |
Advanced science (Weinheim, Baden-Wurttemberg, Germany) - 11(2024), 13 vom: 01. Apr., Seite e2207435 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Chen, Weina [VerfasserIn] |
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| Links: |
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| Themen: |
CUL4B protein, human |
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| Anmerkungen: |
Date Completed 04.04.2024 Date Revised 04.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/advs.202207435 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Defective Homologous Recombination Repair By Up-Regulating Lnc-HZ10/Ahr Loop in Human Trophoblast Cells Induced Miscarriage |
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| 520 | |a Human trophoblast cells are crucial for healthy pregnancy. However, whether the defective homologous recombination (HR) repair of dsDNA break (DSB) in trophoblast cells may induce miscarriage is completely unknown. Moreover, the abundance of BRCA1 (a crucial protein for HR repair), its recruitment to DSB foci, and its epigenetic regulatory mechanisms, are also fully unexplored. In this work, it is identified that a novel lnc-HZ10, which is highly experssed in villous tissues of recurrent miscarriage (RM) vs their healthy control group, suppresses HR repair of DSB in trophoblast cell. Lnc-HZ10 and AhR (aryl hydrocarbon receptor) form a positive feedback loop. AhR acts as a transcription factor to promote lnc-HZ10 transcription. Meanwhile, lnc-HZ10 also increases AhR levels by suppressing its CUL4B-mediated ubiquitination degradation. Subsequently, AhR suppresses BRCA1 transcription; and lnc-HZ10 (mainly 1-447 nt) interacts with γ-H2AX; and thus, impairs its interactions with BRCA1. BPDE exposure may trigger this loop to suppress HR repair in trophoblast cells, possibly inducing miscarriage. Knockdown of murine Ahr efficiently recovers HR repair in placental tissues and alleviates miscarriage in a mouse miscarriage model. Therefore, it is suggested that AhR/lnc-HZ10/BRCA1 axis may be a promising target for alleviation of unexplained miscarriage | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a environmental BaP or BPDE | |
| 650 | 4 | |a female trophoblast cells | |
| 650 | 4 | |a homologous recombination | |
| 650 | 4 | |a miscarriage | |
| 650 | 4 | |a non‐coding RNA lnc‐HZ10 | |
| 650 | 7 | |a Receptors, Aryl Hydrocarbon |2 NLM | |
| 650 | 7 | |a CUL4B protein, human |2 NLM | |
| 650 | 7 | |a Cullin Proteins |2 NLM | |
| 700 | 1 | |a Mi, Chenyang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Yang |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Wenxin |e verfasserin |4 aut | |
| 700 | 1 | |a Xu, Zhongyan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jingsong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Rong |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Manli |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Shukun |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Xiaoqing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Huidong |e verfasserin |4 aut | |
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