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The dimeric deubiquitinase USP28 integrates 53BP1 and MYC functions to limit DNA damage

Chao Jin1,2, Elias Einig1,2, Wenshan Xu3

  • 1Department of Medical Oncology and Pulmonology, University Hospital Tübingen, Otfried-Müller-Str 14, 72076 Tübingen, Germany.

Nucleic Acids Research
|January 16, 2024
PubMed

Insights

USP28 protein dimerization prevents abnormal DNA replication and damage. Stress disrupts this dimerization, increasing replication and DNA damage, revealing a key mechanism for genome stability.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Genetics

Background:

  • DNA replication is a primary source of DNA damage in cancer cells.
  • The oncoprotein MYC, prevalent in cancers, can deregulate DNA replication.
  • USP28, a deubiquitinase targeting MYC, also mediates DNA damage response via 53BP1.

Purpose of the Study:

  • To investigate the biological role of USP28 dimerization.
  • To understand how USP28 dimerization affects MYC activity and DNA replication.
  • To elucidate the interplay between USP28, 53BP1, and DNA damage response.

Main Methods:

  • Investigated USP28 dimerization using biochemical and cellular assays.
  • Assessed the impact of USP28 monomeric versus dimeric forms on MYC recruitment of PAF1c.
  • Examined the effect of genotoxic stress on USP28-53BP1 interaction and USP28 dimer stability.

Main Results:

  • USP28 dimerization limits its activity and restricts MYC-mediated PAF1c recruitment.
  • Monomeric USP28 stabilizes MYC, promoting ectopic DNA synthesis and replication-associated DNA damage.
  • 53BP1 binding stimulates USP28 dimerization; genotoxic stress disrupts this interaction, promoting dimer disassembly.
  • Disassembly of USP28 dimers under stress stimulates MYC-mediated PAF1c recruitment, triggering DNA replication origin firing and exacerbating DNA damage.

Conclusions:

  • USP28 dimerization acts as a critical checkpoint, preventing aberrant DNA replication at transcriptionally active sites.
  • The 53BP1-USP28 interaction regulates USP28 dimer stability in response to genotoxic stress.
  • USP28 dimerization is essential for maintaining genome stability by controlling DNA replication during stress response.

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