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Oxidative DNA Damage Modulates DNA Methylation Pattern in Human Breast Cancer 1 (BRCA1) Gene via the Crosstalk

Zhongliang Jiang1, Yanhao Lai2, Jill M Beaver1

  • 1Biochemistry Ph.D. Program, Florida International University, Miami, FL 33199, USA.

Cells
|January 23, 2020
PubMed

Insights

Oxidative DNA damage triggers dynamic DNA methylation changes in the BRCA1 gene. This involves base excision repair (BER) and DNA methyltransferase 3b (DNMT3b), revealing a novel crosstalk mechanism.

Area of Science:

  • Molecular Biology
  • Epigenetics
  • DNA Repair

Background:

  • DNA damage and base excision repair (BER) influence DNA methylation, but mechanisms are unclear.
  • The tumor suppressor breast cancer 1 (BRCA1) gene's methylation pattern is crucial for its function.
  • Understanding these interactions is vital for cancer research.

Purpose of the Study:

  • To investigate the effects of oxidative DNA damage on BRCA1 gene methylation.
  • To elucidate the molecular mechanisms linking DNA damage, BER, and DNA methylation dynamics.
  • To explore the roles of DNA polymerase β (pol β) and DNA methyltransferase 3b (DNMT3b) in these processes.

Main Methods:

  • Utilized human embryonic kidney (HEK) HEK293H cells.
  • Induced oxidative DNA damage to study its impact on BRCA1 methylation.
  • Investigated the involvement of DNA polymerase β (pol β) and DNA methyltransferase 3b (DNMT3b) using molecular assays.

Main Results:

  • Oxidative DNA damage induced both DNA demethylation and new methylation at BRCA1 CpGs (-189 to +27).
  • DNA demethylation was mediated by pol β-dependent nucleotide misincorporation.
  • New methylation site generation involved coordination between pol β and DNMT3b via enzyme interaction.

Conclusions:

  • Oxidative DNA damage dynamically alters BRCA1 DNA methylation patterns.
  • A novel crosstalk between base excision repair (BER) and de novo DNA methylation is demonstrated.
  • This study reveals a new mechanism connecting DNA damage response and epigenetic regulation.
Keywords:
BRCA1DNA methylationDNA methyltransferase 3bDNA polymerase βbase excision repairde novo DNA methylationoxidative DNA damage

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