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Area of Science:

  • Molecular Biology
  • Epigenetics
  • Cancer Biology

Background:

  • DNA topology is crucial for gene regulation and cellular health.
  • Z-DNA, a left-handed DNA helix, occurs in transcriptionally active regions but its function is unclear.
  • The oncoprotein MYC is implicated in various cancers.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which MYC influences Z-DNA formation.
  • To investigate the role of the chromatin remodeler FACT in Z-DNA dynamics.
  • To determine the functional significance of Z-DNA in transcriptional regulation and MYC-driven cancer.

Main Methods:

  • Genome-wide analysis to identify Z-DNA promoter regions.
  • Biochemical assays to study FACT's interaction with nucleosomes and Z-DNA.
  • Characterization of engineered Z-DNA promoters.
  • Analysis of MYC's role in FACT recruitment and Z-DNA induction.

Main Results:

  • Oncoprotein MYC directly induces Z-DNA formation by recruiting the FACT complex, independent of RNA Polymerase II.
  • FACT facilitates Z-DNA formation through remodeling of H2A/H2B dimers within nucleosomes.
  • Phosphorylation of FACT regulates its liquid-liquid phase separation, enhancing MYC-mediated recruitment.
  • Z-DNA directly promotes RNA Polymerase II loading, thereby increasing transcriptional activity.

Conclusions:

  • MYC-induced Z-DNA formation, mediated by FACT, is a novel mechanism for transcriptional regulation.
  • Z-DNA plays a direct role in facilitating RNA Polymerase II loading and gene expression.
  • This study provides insights into the functional importance of left-handed DNA structures in chromatin biology and MYC-driven cancers.