Dysregulation of PARP2 Contributes to Recurrent Pregnancy Loss by Modulating the Degradation and Subcellular Localization of the Long Non-Coding RNA MALAT1

Abstract

Background: Poly (ADP-ribose) polymerase (PARP) 1 and PARP2 deficiency in the uterus results in the loss of pregnancy. Metastasis associated lung adenocarcinoma transcript 1 (MALAT1), a PARP1 binding nucleus-localized long non-coding ribonucleic acid (RNA), is downregulated in patients with recurrent pregnancy loss (RPL). However, the correlation between MALAT1 and PARPs, and their roles in RPL remain unclear. Methods: In this study, MALAT1, PARP1, and PARP2 levels were examined in the decidua from a cohort consisting of 35 patients with RPL and 15 healthy controls. The interaction between MALAT1 and PARP2 was identified in primary decidual stromal cells using a ribonucleoprotein immunoprecipitation assay and confirmed by RNA pull-down and immunofluorescence. Deoxyribonucleic acid (DNA) damage, cell viability, and apoptosis were examined by immunoblotting, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay, and flow cytometry in PARP2 knockdown cells. Results: MALAT1 and PARP2 levels were downregulated in patients with RPL. The messenger RNA level of PARP2 was positively correlated with MALAT1 levels (r = 0.41, p = 0.013). PARP2 bound MALAT1 close to the 3′ end and colocalizes with it in the cell nucleus. In PARP2 knockdown cells, MALAT1 was re-localized to the nucleus rim and cytoplasm and degraded more quickly. In decidual stromal cells, PARP2 knockdown led to DNA damage, decreased cell viability, and increased apoptosis. Conclusions: We identified the interaction between PARP2 and MALAT1 for the first time and constructed a correlation between MALAT1/PARP2 dysregulation and the occurrence of RPL, which provides new clues for RPL treatment.