Structure-specific endonuclease activity of SNM1A enables processing of a DNA interstrand crosslink

Nucleic Acids Res. 2018 Sep 28;46(17):9057-9066. doi: 10.1093/nar/gky759.

Abstract

DNA interstrand crosslinks (ICLs) covalently join opposing strands, blocking both replication and transcription, therefore making ICL-inducing compounds highly toxic and ideal anti-cancer agents. While incisions surrounding the ICL are required to remove damaged DNA, it is currently unclear which endonucleases are needed for this key event. SNM1A has been shown to play an important function in human ICL repair, however its suggested role has been limited to exonuclease activity and not strand incision. Here we show that SNM1A has endonuclease activity, having the ability to cleave DNA structures that arise during the initiation of ICL repair. In particular, this endonuclease activity cleaves single-stranded DNA. Given that unpaired DNA regions occur 5' to an ICL, these findings suggest SNM1A may act as either an endonuclease and/or exonuclease during ICL repair. This finding is significant as it expands the potential role of SNM1A in ICL repair.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Pairing
  • Base Sequence
  • Benzodiazepinones / chemistry
  • Benzodiazepinones / pharmacology
  • Cell Cycle Proteins
  • Cloning, Molecular
  • Cross-Linking Reagents / chemistry
  • Cross-Linking Reagents / pharmacology
  • DNA Damage
  • DNA Repair*
  • DNA Replication / drug effects
  • DNA, Single-Stranded / chemistry*
  • DNA, Single-Stranded / genetics
  • DNA, Single-Stranded / metabolism
  • Escherichia coli / genetics
  • Escherichia coli / metabolism
  • Exodeoxyribonucleases / genetics*
  • Exodeoxyribonucleases / metabolism
  • Gene Expression
  • Humans
  • Nucleic Acid Conformation / drug effects
  • Oligonucleotides / chemistry*
  • Oligonucleotides / metabolism
  • Plasmids / chemistry
  • Plasmids / metabolism
  • Pyrroles / chemistry
  • Pyrroles / pharmacology
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism

Substances

  • 1,1'-((propane-1,3-diyl)dioxy)bis(7-methoxy-2-methylidene-1,2,3,10,11,11a-hexahydro-5H-pyrrolo(2,1-c)(1,4)benzodiazepin-5,11-dione)
  • Benzodiazepinones
  • Cell Cycle Proteins
  • Cross-Linking Reagents
  • DNA, Single-Stranded
  • Oligonucleotides
  • Pyrroles
  • Recombinant Proteins
  • DCLRE1A protein, human
  • Exodeoxyribonucleases

Grants and funding