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MCL-1 interacts with MOF and BID to regulate H4K16 acetylation and homologous recombination repair

Abid R Mattoo1, John M Jessup1

  • 1Inova Schar Cancer Institute, Falls Church, Virginia, USA.

Cell Biology International
|June 6, 2022
PubMed

Insights

Myeloid cell leukemia-1 (MCL-1) protein interacts with MOF to regulate DNA repair via H4K16 acetylation. MCL-1 and BID cooperate to control the balance between homologous recombination repair and apoptosis.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Cancer Research

Background:

  • The role of myeloid cell leukemia-1 (MCL-1), an anti-apoptotic protein, in DNA repair, specifically homologous recombination (HR), is not fully elucidated.
  • Understanding MCL-1's function in DNA repair is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To investigate the interaction between MCL-1 and MOF (Males absent On First) in regulating H4K16 acetylation.
  • To determine how this interaction influences HR repair under replication stress induced by Hydroxyurea (HU).
  • To explore the interplay between MCL-1, BID (BH3-interacting domain death agonist), HR repair, and apoptosis.

Main Methods:

  • Co-immunoprecipitation assays were performed on cancer cells treated with HU to identify protein complexes involving MCL-1 and MOF.
  • Knockdown and re-expression experiments were used to assess the role of MCL-1 in H4K16 acetylation.
  • Clonogenic survival assays and direct repeats-green fluorescent protein assays were employed to evaluate HR repair efficiency.
  • Western blotting was used to measure the phosphorylation levels of ATR, Chk1, and RPA.

Main Results:

  • MCL-1 was found to form a complex with MOF and BID in cells treated with HU.
  • MCL-1 was shown to regulate H4K16 acetylation during HU-induced replication stress; MCL-1 knockdown decreased acetylation, while re-expression restored it.
  • Knockdown of BID rescued clonogenic survival in MCL-1 depleted cells, correlating with reduced Caspase 3/7 activity.
  • Cells depleted of both MCL-1 and BID exhibited enhanced HR repair efficiency and increased phosphorylation of ATR, Chk1, and RPA.

Conclusions:

  • MCL-1 collaborates with MOF to regulate homologous recombination repair through H4K16 acetylation.
  • MCL-1 and BID cooperate in managing the crosstalk between homologous recombination repair and apoptosis.
  • This study provides novel insights into the molecular mechanisms governing DNA repair and cell survival pathways.
Keywords:
H4K16 acetylationHR repairMCL-1MOFNHEJ

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