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功能获得性 GINS3 变异可改变 DNA 复制并导致 Meier-Gorlin 综合征。

Hypomorphic GINS3 variants alter DNA replication and cause Meier-Gorlin syndrome.

机构信息

Maisonneuve-Rosemont Hospital Research Center, Montreal, Quebec, Canada.

Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, Ontario, Canada.

出版信息

JCI Insight. 2022 May 23;7(10):e155648. doi: 10.1172/jci.insight.155648.

DOI:10.1172/jci.insight.155648
PMID:35603789
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9215265/
Abstract

The eukaryotic CDC45/MCM2-7/GINS (CMG) helicase unwinds the DNA double helix during DNA replication. The GINS subcomplex is required for helicase activity and is, therefore, essential for DNA replication and cell viability. Here, we report the identification of 7 individuals from 5 unrelated families presenting with a Meier-Gorlin syndrome-like (MGS-like) phenotype associated with hypomorphic variants of GINS3, a gene not previously associated with this syndrome. We found that MGS-associated GINS3 variants affecting aspartic acid 24 (D24) compromised cell proliferation and caused accumulation of cells in S phase. These variants shortened the protein half-life, altered key protein interactions at the replisome, and negatively influenced DNA replication fork progression. Yeast expressing MGS-associated variants of PSF3 (the yeast GINS3 ortholog) also displayed impaired growth, S phase progression defects, and decreased Psf3 protein stability. We further showed that mouse embryos homozygous for a D24 variant presented intrauterine growth retardation and did not survive to birth, and that fibroblasts derived from these embryos displayed accelerated cellular senescence. Taken together, our findings implicate GINS3 in the pathogenesis of MGS and support the notion that hypomorphic variants identified in this gene impaired cell and organismal growth by compromising DNA replication.

摘要

真核细胞的 CDC45/MCM2-7/GINS（CMG）解旋酶在 DNA 复制过程中解开 DNA 双链。GINS 亚基复合物是解旋酶活性所必需的，因此对 DNA 复制和细胞存活至关重要。在这里，我们报告了 5 个不相关的家庭中的 7 个个体，他们表现出类似于 Meier-Gorlin 综合征（MGS-样）的表型，与 GINS3 的低功能变体相关，GINS3 是以前与该综合征无关的基因。我们发现，影响天冬氨酸 24（D24）的与 MGS 相关的 GINS3 变体削弱了细胞增殖能力，并导致 S 期细胞积累。这些变体缩短了蛋白质半衰期，改变了复制体中的关键蛋白相互作用，并对 DNA 复制叉的进展产生负面影响。表达与 MGS 相关的 PSF3 变体（酵母 GINS3 同源物）的酵母也表现出生长受损、S 期进展缺陷和 Psf3 蛋白稳定性降低。我们进一步表明，D24 变体纯合的小鼠胚胎表现出宫内生长迟缓，并且不能存活到出生，并且这些胚胎衍生的成纤维细胞表现出加速的细胞衰老。总之，我们的研究结果表明 GINS3 参与了 MGS 的发病机制，并支持这样的观点，即该基因中鉴定的低功能变体通过削弱 DNA 复制而损害细胞和机体生长。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/da418f5aad42/jciinsight-7-155648-g210.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/05dde01d67f8/jciinsight-7-155648-g203.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/2a5ba9972067/jciinsight-7-155648-g205.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/4cd74ad34fc7/jciinsight-7-155648-g208.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/4790e2481e74/jciinsight-7-155648-g209.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/da418f5aad42/jciinsight-7-155648-g210.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/05dde01d67f8/jciinsight-7-155648-g203.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/67c061b41e9d/jciinsight-7-155648-g204.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/2a5ba9972067/jciinsight-7-155648-g205.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/428ad107ed82/jciinsight-7-155648-g206.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/eb555040439a/jciinsight-7-155648-g207.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/4cd74ad34fc7/jciinsight-7-155648-g208.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/4790e2481e74/jciinsight-7-155648-g209.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/124f/9215265/da418f5aad42/jciinsight-7-155648-g210.jpg

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