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MPTAC links alkylation damage signaling to sterol biosynthesis

Tamaki Suganuma1, Jerry L Workman1

  • 1Stowers Institute for Medical Research, 1000 E. 50th Street, Kansas City, MO, 64110, USA.

Redox Biology
|February 21, 2022
PubMed

Insights

DNA repair protein MSH6 stabilization involves Molybdopterin synthase associating complex (MPTAC) and ATAC. This interaction reduces inflammation and reactive oxygen species (ROS), impacting Fragile X-associated disorders (FXD).

Area of Science:

  • Molecular Biology
  • Immunology
  • Genetics

Background:

  • Reactive oxygen species (ROS) overproduction contributes to inflammation and mutagenesis.
  • The role of DNA damage response (DDR) in immune responses is not well understood.

Purpose of the Study:

  • To investigate the role of the mismatch repair (MMR) protein MSH6 in DNA damage response and immune regulation.
  • To explore the relationship between MSH6, Molybdopterin synthase associating complex (MPTAC), and Ada2a-containing histone acetyltransferase complex (ATAC).
  • To examine the implications of these interactions in Fragile X-associated disorders (FXD).

Main Methods:

  • Investigated MSH6 stabilization via interactions with MPTAC and ATAC following alkylation damage.
  • Assessed MSH6's role in promoting sterol biosynthesis through the mevalonate pathway.
  • Analyzed inflammatory responses (xanthine oxidase activity) in Lymphoblastoid Cell Lines (LCLs) from FXD patients.
  • Examined MPTAC and ATAC complex integrity and MSH6 interactions in FXD LCLs.

Main Results:

  • MSH6 stabilization requires MPTAC and ATAC interactions.
  • MSH6 promotes sterol biosynthesis dependent on MPTAC and ATAC.
  • MPTAC activity reduces ROS levels, contributing to anti-inflammation.
  • Elevated inflammation and increased alkylating agents observed in some FXD patient LCLs.
  • MPTAC disruption or loss of MSH6-ATAC interaction in FXD LCLs suggests impaired alkylation damage resistance.

Conclusions:

  • The association between MMR proteins (MSH6), MPTAC, and ATAC is crucial for anti-inflammation and reducing ROS.
  • Dysregulation of MPTAC and ATAC in FXD patients may lead to increased alkylation damage and resistance.
  • These findings highlight a novel link between DNA repair pathways and immune response modulation in FXD.
Keywords:
ATACAlkylation damageFragile X-associated disordersMPTACMSH6Mevalonate pathwaySterol biosynthesis

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