PARP1 negatively regulates MAPK signaling by impairing BRAF-X1 translation

J Hematol Oncol. 2023 Apr 3;16(1):33. doi: 10.1186/s13045-023-01428-2.

Abstract

In human cells BRAF oncogene is invariably expressed as a mix of two coding transcripts: BRAF-ref and BRAF-X1. These two mRNA isoforms, remarkably different in the sequence and length of their 3'UTRs, are potentially involved in distinct post-transcriptional regulatory circuits. Herein, we identify PARP1 among the mRNA Binding Proteins that specifically target the X1 3'UTR in melanoma cells. Mechanistically, PARP1 Zinc Finger domain down-regulates BRAF expression at the translational level. As a consequence, it exerts a negative impact on MAPK pathway, and sensitizes melanoma cells to BRAF and MEK inhibitors, both in vitro and in vivo. In summary, our study unveils PARP1 as a negative regulator of the highly oncogenic MAPK pathway in melanoma, through the modulation of BRAF-X1 expression.

Keywords: BRAF-X1; MAPK pathway; Melanoma; PARP1; Vemurafenib; mRBP.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Indoles / pharmacology
  • MAP Kinase Signaling System
  • Melanoma* / genetics
  • Melanoma* / metabolism
  • Poly (ADP-Ribose) Polymerase-1 / genetics
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf* / genetics
  • Proto-Oncogene Proteins B-raf* / metabolism
  • Sulfonamides / pharmacology
  • Vemurafenib

Substances

  • Vemurafenib
  • Proto-Oncogene Proteins B-raf
  • Indoles
  • Sulfonamides
  • Protein Kinase Inhibitors
  • BRAF protein, human
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1