New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family

Bouali, Nouha; Francou, Bruno; Bouligand, Jérôme; Imanci, Dilek; Dimassi, Sarra; Tosca, Lucie; Zaouali, Monia; Mougou, Soumaya; Young, Jacques; Saâd, Ali; Guiochon‐Mantel, Anne

doi:10.1016/j.fertnstert.2017.07.015

Cited by 61 publications

(48 citation statements)

References 20 publications

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“…We used genomic data spanning multiple data types to cross validate our findings on estrogen loss and AD risk. We found excess deleterious singleton mutations in the ovarian failure [60,68–71] and early menopause [61,72–76] gene MCM8 (Table 2, Supplementary Table 11), providing robust support for our hypothesis that estrogen loss at menopause confers increased vulnerability to AD in women. This finding fits with previous studies that have linked surgical menopause to doubled lifetime risk for dementia [23], increased risk for AD neuropathology [22] and cognitive decline [22].…”

Section: Discussionsupporting

confidence: 61%

Estrogen activates Alzheimer's disease genes

Ratnakumar¹,

Zimmerman²,

Jordan

et al. 2019

A&D Transl Res & Clin Interv

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IntroductionWomen are at increased risk for Alzheimer's disease (AD), but the reason why remains unknown. One hypothesis is that low estrogen levels at menopause increases vulnerability to AD, but this remains unproven.MethodsWe compared neuronal genes upregulated by estrogen in ovariectomized female rhesus macaques with a database of >17,000 diverse gene sets and applied a rare variant burden test to exome sequencing data from 1208 female AD patients with the age of onset < 75 years and 2162 female AD controls.ResultsWe found a striking overlap between genes upregulated by estrogen in macaques and genes downregulated in the human postmortem AD brain, and we found that estrogen upregulates the APOE gene and that progesterone acts antagonistically to estrogen genome-wide. We also found that female patients with AD have excess rare mutations in the early menopause gene MCM8.DiscussionWe show with genomic data that the menopausal loss of estrogen could underlie the increased risk for AD in women.

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Section: Discussionsupporting

confidence: 61%

Estrogen activates Alzheimer's disease genes

Ratnakumar¹,

Zimmerman²,

Jordan

et al. 2019

A&D Transl Res & Clin Interv

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“…Having demonstrated the functional cooperation between MCM8IP and MCM8-9, we examined whether POI-associated MCM8 mutations (i.e., P149R, H161P, E341K, Fig. 7e) [48][49][50][51] could disrupt the interaction of MCM8 with MCM8IP. To this end, we expressed either WT or mutant MCM8-HA in HEK293T cells and subjected the cell lysates to anti-HA immunoprecipitation.…”

Section: Resultsmentioning

confidence: 99%

“…In line with these findings, Mcm8-9-null mice exhibit infertility due to gametogenesis defects 11,12 . Interestingly, MCM8 and MCM9 mutations in patient-derived cells cause elevated ICLinduced chromosomal instability 50,51,66 , suggesting that POI may be a consequence of defective MCM8-9-dependent HR events. Our and others' work implicate the MCM8IP-MCM8-9 complex in HR as well as murine fertility 52 , raising the prospect that mutations in MCM8IP may cause POI.…”

Section: Discussionmentioning

confidence: 99%

MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

et al. 2020

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Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. Here we characterize C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a DNA repair factor involved in HR. MCM8IPdeficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition. Importantly, we report that MCM8IP directly associates with MCM8-9, a helicase complex mutated in primary ovarian insufficiency, and RPA1. We additionally show that the interactions of MCM8IP with MCM8-9 and RPA facilitate HR and promote replication fork progression and cellular viability in response to treatment with crosslinking agents. Mechanistically, MCM8IP stimulates the helicase activity of MCM8-9. Collectively, our work identifies MCM8IP as a key regulator of MCM8-9-dependent DNA synthesis during DNA recombination and replication.

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“…This phenotype is consistent with the sterility of female MCM8-null mice, which exhibit defects in gametogenesis due to impaired HR during meiosis 13 . Having demonstrated the functional cooperation between MCM8IP and MCM8-9, we examined whether POIassociated MCM8 mutations (i.e., P149R, H161P, E341K, Figure 7E) [39][40][41][42] could disrupt the interaction of MCM8 with MCM8IP. To this end, we expressed either WT or mutant HA-MCM8 in HEK293T cells and subjected the cell lysates to anti-HA immunoprecipitation.…”

Section: Poi Patient Mutations Disrupt the Mcm8ip-mcm8 Interactionmentioning

confidence: 99%

“…POI is an infertility syndrome caused by mutations in at least 60 genes 71 . Among these genes are MCM8 and MCM9, whose mutations in patient-derived cells cause elevated ICL-induced chromosomal instability 41,42,72 . MCM8-9-null mice exhibit infertility due to gametogenesis defects 13,14 .…”

Section: Mcm8ip and Primary Ovarian Insufficiencymentioning

confidence: 99%

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

Huang

Taglialatela

Acharya

et al. 2019

Preprint

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Homologous recombination (HR) mediates the error-free repair of DNA double-strand breaks to maintain genomic stability. HR is carried out by a complex network of DNA repair factors. Here we identify C17orf53/MCM8IP, an OB-fold containing protein that binds ssDNA, as a novel DNA repair factor involved in HR. MCM8IP-deficient cells exhibit HR defects, especially in long-tract gene conversion, occurring downstream of RAD51 loading, consistent with a role for MCM8IP in HR-dependent DNA synthesis. Moreover, loss of MCM8IP confers cellular sensitivity to crosslinking agents and PARP inhibition.Importantly, we identify a direct interaction with MCM8-9, a putative helicase complex mutated in Primary Ovarian Insufficiency, that is crucial for MCM8IP's ability to promote resistance to DNA damaging agents. In addition to its association with MCM8-9, MCM8IP also binds directly to RPA1. We show that the interactions of MCM8IP with both MCM8-9 and RPA are required to maintain replication fork progression in response to treatment with crosslinking agents. Collectively, our work identifies MCM8IP as a key regulator of DNA damage-associated DNA synthesis during DNA recombination and replication.

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New MCM8 mutation associated with premature ovarian insufficiency and chromosomal instability in a highly consanguineous Tunisian family

Abstract: Our findings provide additional support to the view that MCM8 mutations are involved in the primary ovarian insufficiency phenotype.

Cited by 61 publications

References 20 publications

Estrogen activates Alzheimer's disease genes

Estrogen activates Alzheimer's disease genes

MCM8IP activates the MCM8-9 helicase to promote DNA synthesis and homologous recombination upon DNA damage

Identification of MCM8IP, an interactor of MCM8-9 and RPA1 that promotes homologous recombination and DNA synthesis in response to DNA damage

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