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HMGB1 interacts with XPA to facilitate the processing of DNA interstrand crosslinks in human cells

Anirban Mukherjee1, Karen M Vasquez2

  • 1Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Dell Pediatric Research Institute, 1400 Barbara Jordan Boulevard, Austin, TX 78723, USA.

Nucleic Acids Research
|November 19, 2015
PubMed

Insights

High mobility group box 1 (HMGB1) aids DNA repair in human cells by recognizing DNA interstrand crosslinks (ICLs). HMGB1 works with XPA to promote accurate ICL repair, preventing harmful mutations during chemotherapy.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • DNA interstrand crosslinks (ICLs) are cytotoxic DNA lesions caused by chemotherapy agents.
  • Understanding ICL recognition and repair in human cells is crucial but incomplete.
  • Previous studies showed High Mobility Group Box 1 (HMGB1) aids ICL repair in mouse cells.

Purpose of the Study:

  • To investigate the role of HMGB1 in recognizing and processing ICLs in human cells.
  • To determine how HMGB1 influences ICL-induced mutagenesis and mutation spectra.
  • To elucidate the interaction between HMGB1 and XPA in ICL repair.

Main Methods:

  • Depletion of HMGB1 in human cells and analysis of ICL-induced mutations.
  • Assessment of mutation spectra in HMGB1-depleted and XPA-deficient cells.
  • Co-depletion experiments to study XPA and HMGB1 recruitment to ICLs.
  • In vitro supercoiling assays using ICL-containing plasmids and HeLa cell extracts.

Main Results:

  • HMGB1 depletion increased ICL-induced mutagenesis in human cells.
  • HMGB1 depletion altered mutation spectra in XPA-deficient cells (T→A to T→G).
  • XPA and HMGB1 recruitment to ICLs was found to be co-dependent.
  • HMGB1 was shown to introduce negative supercoils into ICL-containing plasmids.

Conclusions:

  • HMGB1 recognizes ICLs in human cells and functions with XPA.
  • HMGB1 facilitates a favorable DNA structure for efficient ICL repair.
  • HMGB1 plays a significant role in preventing mutagenesis during ICL repair processing.

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