Metnase and EEPD1: DNA Repair Functions and Potential Targets in Cancer Therapy

Jac A. Nickoloff, Neelam Sharma, Lynn Taylor, Sage J. Allen, Suk Hee Lee, Robert Hromas

Research output: Contribution to journalReview articlepeer-review

Abstract

Cells respond to DNA damage by activating signaling and DNA repair systems, described as the DNA damage response (DDR). Clarifying DDR pathways and their dysregulation in cancer are important for understanding cancer etiology, how cancer cells exploit the DDR to survive endogenous and treatment-related stress, and to identify DDR targets as therapeutic targets. Cancer is often treated with genotoxic chemicals and/or ionizing radiation. These agents are cytotoxic because they induce DNA double-strand breaks (DSBs) directly, or indirectly by inducing replication stress which causes replication fork collapse to DSBs. EEPD1 and Metnase are structure-specific nucleases, and Metnase is also a protein methyl transferase that methylates histone H3 and itself. EEPD1 and Metnase promote repair of frank, two-ended DSBs, and both promote the timely and accurate restart of replication forks that have collapsed to single-ended DSBs. In addition to its roles in HR, Metnase also promotes DSB repair by classical non-homologous recombination, and chromosome decatenation mediated by TopoIIα. Although mutations in Metnase and EEPD1 are not common in cancer, both proteins are frequently overexpressed, which may help tumor cells manage oncogenic stress or confer resistance to therapeutics. Here we focus on Metnase and EEPD1 DNA repair pathways, and discuss opportunities for targeting these pathways to enhance cancer therapy.

Original languageEnglish (US)
Article number808757
JournalFrontiers in Oncology
Volume12
DOIs
StatePublished - Jan 28 2022
Externally publishedYes

Keywords

  • DNA damage
  • DNA double-strand breaks
  • DNA repair
  • chromosome decatenation
  • genome instability
  • homologous recombination
  • non-homologous end-joining

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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