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晚期糖基化终产物受体（RAGE）在病理性胎盘和滋养层细胞中双链断裂（DSBs）检测中的作用

A Role for RAGE in DNA Double Strand Breaks (DSBs) Detected in Pathological Placentas and Trophoblast Cells.

机构信息

Lung and Placenta Research Laboratory, Department of Physiology and Developmental Biology, Brigham Young University, Provo, UT 84602, USA.

出版信息

Cells. 2021 Apr 9;10(4):857. doi: 10.3390/cells10040857.

DOI:10.3390/cells10040857
PMID:33918759
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8069300/
Abstract

Impaired DNA damage responses are associated with several diseases, including pregnancy complications. Recent research identified an ATM-kinase dependent function for the nuclear isoform of the receptor for advanced glycation end-products (RAGE) during double strand break (DSB)-repair. RAGE contributes to end-resectioning of broken DNA sites by binding with the MRE11-Rad50-Nbs1 (MRN) complex. Placental research is limited regarding the impact of genomic instability and the mechanism for potential repair. We tested the hypothesis regarding the involvement of RAGE during the repair of placental DNA-DSBs. We first identified that the pregnancy complications of PE and preterm labor (PTL) experience loss of genomic integrity and an in vitro trophoblast cell model was used to characterize trophoblast DSBs. Colocalized immunofluorescence of γ-H2AX and RAGE support the potential involvement of RAGE in cellular responses to DNA-DSBs. Immunoblotting for both molecules in PE and PTL placenta samples and in trophoblast cells validated a connection. Co-immunoprecipitation studies revealed interactions between RAGE and pATM and MRE11 during DNA-DSBs. Reduced cellular invasion confirmed the role of genomic instability in trophoblastic function. Collectively, these experiments identified genomic instability in pregnancy complications, the impact of defective DNA on trophoblast function, and a possible RAGE-mediated mechanism during DNA-DSB repair.

摘要

DNA 损伤反应受损与多种疾病有关，包括妊娠并发症。最近的研究发现，在双链断裂 (DSB) 修复过程中，晚期糖基化终产物 (RAGE) 的受体的核异构体具有 ATM 激酶依赖性功能。RAGE 通过与 MRE11-Rad50-Nbs1 (MRN) 复合物结合，有助于对断裂 DNA 位点进行末端切除。关于基因组不稳定性的影响和潜在修复机制的胎盘研究有限。我们检验了关于 RAGE 在胎盘 DNA-DSB 修复过程中参与的假设。我们首先确定了 PE 和早产 (PTL) 的妊娠并发症经历了基因组完整性的丧失，并且使用体外滋养层细胞模型来表征滋养层 DSB。γ-H2AX 和 RAGE 的共聚焦免疫荧光支持 RAGE 参与细胞对 DNA-DSB 的反应的潜力。PE 和 PTL 胎盘样本和滋养层细胞中的这两种分子的免疫印迹验证了联系。共免疫沉淀研究揭示了 DNA-DSB 过程中 RAGE 与 pATM 和 MRE11 之间的相互作用。细胞侵袭减少证实了基因组不稳定性在滋养层功能中的作用。总之，这些实验确定了妊娠并发症中的基因组不稳定性、DNA 缺陷对滋养层功能的影响以及 DNA-DSB 修复过程中可能的 RAGE 介导机制。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/b474734ff133/cells-10-00857-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/c0635fb7427f/cells-10-00857-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/95f198a36447/cells-10-00857-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/b474734ff133/cells-10-00857-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/67145e136938/cells-10-00857-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/63f6cc28a984/cells-10-00857-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/96b6cac3b842/cells-10-00857-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/ca92fba05cc1/cells-10-00857-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/060a0ed1c729/cells-10-00857-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/f24b393438ce/cells-10-00857-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/c0635fb7427f/cells-10-00857-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/95f198a36447/cells-10-00857-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/c335/8069300/b474734ff133/cells-10-00857-g009.jpg

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