Related Experiment Video

Updated: Feb 17, 2026

Author Spotlight: Genetically Engineered Mouse Models and Pathological Characterization of Neurofibromatosis Type 1 Associated Tumors
08:57

Author Spotlight: Genetically Engineered Mouse Models and Pathological Characterization of Neurofibromatosis Type 1 Associated Tumors

Published on: May 17, 2024

2.7K

Alternative NHEJ pathway proteins as components of MYCN oncogenic activity in human neural crest stem cell

Erika A Newman1, Sahiti Chukkapalli2, Daniela Bashllari2

  • 1Department of Surgery, C.S. Mott Children and Women's Hospital, Mott Solid Tumor Oncology Program, The University of Michigan Medical School, Ann Arbor, MI, USA. eanewman@med.umich.edu.

Cell Death & Disease
|December 15, 2017
PubMed

Insights

Neuroblastoma cancer cells utilize the alternative nonhomologous end-joining (alt-NHEJ) DNA repair pathway for survival. This pathway, originating from neural crest stem cells (NCSCs), is upregulated by the MYCN oncogene, promoting tumor growth and resistance to cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Neuroblastoma, a cancer of neural crest stem cell (NCSC) lineage, is driven by signaling pathways regulating NCSC differentiation.
  • The MYCN oncogene plays a critical role in balancing proliferation, differentiation, and cell death in both normal NCSCs and high-risk neuroblastoma.
  • MYCN-amplified neuroblastoma employs a survival mechanism involving the upregulation of the alternative nonhomologous end-joining (alt-NHEJ) DNA repair pathway to circumvent cell death.

Purpose of the Study:

  • To investigate the hypothesis that alt-NHEJ overexpression in neuroblastoma is a cancer cell survival mechanism originating from NCSC DNA repair systems.
  • To establish and utilize a human NCSC model to study the role of MYCN and alt-NHEJ in neuroblastoma development.

Main Methods:

  • Generation of a human NCSC model with inducible MYCN expression, leading to an immortalized phenotype and metastatic tumor formation in mice.
  • Analysis of critical alt-NHEJ components (DNA Ligase III, DNA Ligase I, PARP1) expression in normal NCSCs during differentiation and in MYCN-expressing cells.
  • Utilizing siRNA knockdown of alt-NHEJ components to assess their impact on NCSC proliferation, invasion, migration, and neuroblastoma marker expression.

Main Results:

  • Critical alt-NHEJ components were highly expressed in early normal NCSCs and decreased with terminal differentiation.
  • Constitutive MYCN expression maintained high alt-NHEJ protein levels, preserving the immature neural phenotype.
  • siRNA-mediated knockdown of alt-NHEJ components reversed MYCN-driven proliferation, invasion, and migration, and significantly decreased neuroblastoma markers (TH, Phox2b, TRKB).

Conclusions:

  • The study establishes a link between MYCN and alt-NHEJ expression in neuroblastoma initiation, suggesting a developmental origin for this cancer survival mechanism.
  • Overexpression of alt-NHEJ components in neuroblastoma represents a survival strategy derived from NCSC DNA repair pathways.
  • These findings highlight the importance of alt-NHEJ repair mechanics in neuroblastoma DNA maintenance and provide a basis for future therapeutic strategies.

More Related Videos

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells09:37

Defining Gene Functions in Tumorigenesis by Ex vivo Ablation of Floxed Alleles in Malignant Peripheral Nerve Sheath Tumor Cells

Published on: August 25, 2021

2.2K
An Enzyme- and Serum-free Neural Stem Cell Culture Model for EMT Investigation Suited for Drug Discovery07:43

An Enzyme- and Serum-free Neural Stem Cell Culture Model for EMT Investigation Suited for Drug Discovery

Published on: August 23, 2016

10.5K

Related Concept Videos

Induced Pluripotent Stem Cells01:06

Induced Pluripotent Stem Cells

Stem cells are undifferentiated cells that divide and produce different cell types. Ordinarily, cells that have differentiated into a specific cell type are terminally differentiated; however, scientists have found a way to reprogram these mature cells so that they dedifferentiate and return to an unspecialized, proliferative state. These cells are pluripotent like embryonic stem cells—able to produce all cell types—and are called induced pluripotent stem cells (iPSCs).
Somatic...
5.7K
Notch Signaling Pathway03:14

Notch Signaling Pathway

The Notch signaling pathway is a major intracellular signaling pathway that is highly conserved over a broad spectrum of metazoan species. It stands unique from other intracellular signaling mechanisms in animals because notch protein itself acts as the receptor as well as the primary signaling molecule.
The Notch gene came into the limelight in 1914 after the discovery that its mutation in Drosophila melanogaster leads to a serrated (or "notched") wing margin phenotype. It was not...
6.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
5.3K
Canonical Wnt Signaling Pathway02:54

Canonical Wnt Signaling Pathway

The gene encoding the main signaling molecules of the Wnt signaling pathways (the Wnt proteins) was discovered almost four decades ago by Nüsslein-Volhard and Wieschaus. They identified and originally named the gene "wingless" (wg) after a phenotype discovered during their landmark genetic screen in Drosophila for body pattern defects. At around the same time, another researcher named Harold Varmus found that a murine tumor virus activates the mammalian wg homolog, Int-1, which...
10.7K