MND1 and PSMC3IP control PARP inhibitor sensitivity in mitotic cells.

The PSMC3IP-MND1 heterodimer promotes meiotic D loop formation before DNA strand exchange. In genome-scale CRISPR-Cas9 mutagenesis and interference screens in mitotic cells, depletion of PSMC3IP or MND1 causes sensitivity to poly (ADP-Ribose) polymerase inhibitors (PARPi) used in cancer treatment. PSMC3IP or MND1 depletion also causes ionizing radiation sensitivity. These effects are independent of PSMC3IP/MND1's role in mitotic alternative lengthening of telomeres. PSMC3IP- or MND1-depleted cells accumulate toxic RAD51 foci in response to DNA damage, show impaired homology-directed DNA repair, and become PARPi sensitive, even in cells lacking both BRCA1 and TP53BP1. Epistasis between PSMC3IP-MND1 and BRCA1/BRCA2 defects suggest that abrogated D loop formation is the cause of PARPi sensitivity. Wild-type PSMC3IP reverses PARPi sensitivity, whereas a PSMC3IP p.Glu201del mutant associated with D loop defects and ovarian dysgenesis does not. These observations suggest that meiotic proteins such as MND1 and PSMC3IP have a greater role in mitotic DNA repair.

Biallelic mutations in PSMC3IP are associated with secondary amenorrhea: expanding the spectrum of premature ovarian insufficiency.

Premature ovarian insufficiency (POI) has a strong genetic component, but, in most cases, the etiology remains unidentified. PSMC3IP is an autosomal recessive gene for POI and ovarian dysgenesis, and so far, biallelic mutations in this gene have been described in only four independent families, with all affected members showing primary amenorrhea. Here, we report on the first family with recessive variants in the PSMC3IP gene and POI in a patient with secondary amenorrhea. Whole-exome sequencing (WES) was performed on a 29-year-old woman with secondary amenorrhea and POI; she was found to carry compound heterozygous variants in the PSMC3IP gene: c.206_208delAGA and c.189 G > T. Her younger sister, who also presented with a suspect of POI due to infertility and very low levels of anti-müllerian hormone (AMH), was found to carry the same PSMC3IP variants. Our case report shows the importance to include PSMC3IP in designed POI NGS panels or in WES/WGS studies in patients with either primary or secondary amenorrhea.

Two novel biallelic mutations in PSMC3IP in a patient affected by premature ovarian insufficiency.

Premature ovarian insufficiency (POI) is a heterogeneous condition occurring when a woman experiences a loss of ovarian activity before the age of 40. POI is one of the most common reproductive endocrine diseases in women of childbearing age. The present study investigated the clinical manifestations and genetic features of a Chinese patient affected by POI. Next­generation whole­exome capture sequencing with Sanger direct sequencing were applied to the proband and her clinically unaffected family members. Two novel compound heterozygous mutations were identified in PSMC3IP. The first was a splicing mutation (c.597+1G>T) that was inherited from her father, whereas the second mutation (c.268G>C p.D90H) was discovered in both her mother and younger sister. The two mutations were co­segregated with the disease phenotype in the family. In conclusion, the findings of the present study further support the key role of PSMC3IP in the etiology of POI and provide a novel insight into elucidating the mechanisms of female infertility.

Genetic study on a consanguineous Chinese family with premature ovarian insufficiency caused by a missense mutation of PSMC3IP gene / 中国医师杂志

Objective:To explore the genetic etiology for a premature ovarian insufficiency (POI) patient from a consanguineous Chinese family, and to provide basis for genetic counseling and fertility counseling.Methods:Whole-exome sequencing was performed using DNA extracted from the blood sample of POI patient. Suspected pathogenic mutation was analyzed by bioinformatics methods and verified by Sanger sequencing. The pathogenicity of the variation was assessed according to the ACMG genetic variation classification criteria and guidelines.Results:A homozygous variation, c. 32G>T (p.G11V), of PSMC3IP was identified in the patient. Bioinformatics analysis revealed that the variation was conserved in different animal species, and this variation was classified as possible pathogenic variation according to the ACMG genetic variation classification criteria and guidelines.Conclusions:The homozygous missense variation of PSMC3IP is the cause of the POI patient in this family. We are reporting for the first time the missense variation in PSMC3IP gene caused POI, which enriched the mutation spectrum of PSMC3IP and provided the basis for genetic counseling and fertility guidance of this family.

Knockdown of PSMC3IP suppresses the proliferation and xenografted tumorigenesis of hepatocellular carcinoma cell.

Hepatocellular carcinoma (HCC) is the fifth most frequent malignancy and the second leading cause of cancer-related death worldwide. Proteasome 26S subunit ATPase 3 interacting protein (PSMC3IP) is an oncogene in breast cancer, while its role in HCC remains unclear. Here, we found that PSMC3IP was critical for the cell proliferation and tumorigenic capacity of HCC cells. Upregulation of PSMC3IP was observed in HCC specimens, and high PSMC3IP expression predicted poor overall survival of HCC patients. In vitro, knockdown of PSMC3IP blunted the proliferation and colony formation of BEL-7404 and SMMC-7721 cells. Likewise, PSMC3IP silencing suppressed the xenografted tumor development of BEL-7404 cells. Mechanistically, apoptosis was enhanced after PSMC3IP knockdown in both BEL-7404 and SMMC-7721 cells. At the molecular level, TP53 and GNG4 were upregulated and eukaryotic translation initiation factor 4E (EIF4E) and insulin like growth factor 1 receptor (IGF1R) were downregulated in shPSMC3IP compared with shCtrl BEL-7404 cells. Therefore, targeting PSMC3IP maybe a promising strategy for HCC.