Stress-Induced Changes in Nucleocytoplasmic Localization of Crucial Factors in Gene Expression Regulation

Int J Mol Sci. 2024 Mar 31;25(7):3895. doi: 10.3390/ijms25073895.

Abstract

This study investigates the toxic effect of harmful materials, unfiltered by the placenta, on neonatal umbilical cord (UC) vessels, focusing on stress-induced adaptations in transcriptional and translational processes. It aims to analyze changes in pathways related to mRNA condensate formation, transcriptional regulation, and DNA damage response under maternal smoking-induced stress. UC vessels from neonates born to smoking (Sm) and nonsmoking mothers (Ctr) were examined. Immunofluorescence staining and confocal microscopy assessed the localization of key markers, including Transcription Complex Subunit 1 (CNOT1) and the largest subunit of RNA polymerase II enzyme (RPB1). Additionally, markers of DNA damage response, such as Poly(ADP-ribose) polymerase-1, were evaluated. In Sm samples, dissolution of CNOT1 granules in UC vessels was observed, potentially aiding stalled translation and enhancing transcription via RPB1 assembly and translocation. Control vessels showed predominant cytoplasmic RPB1 localization. Despite adaptive responses, Sm endothelial cells exhibited significant damage, indicated by markers like Poly(ADP-ribose) polymerase-1. Ex vivo metal treatment on control vessels mirrored Sm sample alterations, emphasizing marker roles in cell survival under toxic exposure. Maternal smoking induces specific molecular adaptations in UC vessels, affecting mRNA condensate formation, transcriptional regulation, and DNA damage response pathways. Understanding these intricate molecular mechanisms could inform interventions to improve neonatal health outcomes and mitigate adverse effects of toxic exposure during pregnancy.

Keywords: CNOT1 (carbon catabolite repression-negative on TATA-less); PARP-1 (poly-(ADP-ribose) polymerase-1); RPB1 (the largest subunit of RNA polymerase II enzyme); blood vessels; fetal development; maternal smoking; rescue mechanism.

MeSH terms

  • Cone-Rod Dystrophies*
  • Endothelial Cells*
  • Female
  • Gene Expression Regulation
  • Humans
  • Infant, Newborn
  • Poly(ADP-ribose) Polymerases
  • Pregnancy
  • RNA, Messenger / genetics
  • Transcription Factors
  • Transcription, Genetic

Substances

  • Poly(ADP-ribose) Polymerases
  • RNA, Messenger
  • CNOT1 protein, human
  • Transcription Factors

Grants and funding

This research was funded by the European Union and the Hungarian Government in the framework of the GINOP-2.3.2-15-2016-00035 project and by the OTKA-142961 grant from the Hungarian National Research, Development and Innovation Office.