title: Emerging roles of the nucleolus in regulating the DNA damage response: the noncanonical DNA repair enzyme APE1/Ref-1 as a paradigmatical example.
abstract: CONCLUSIONS
  An emerging concept in DNA repair mechanisms is the evidence that some key enzymes, besides their role in the maintenance of genome stability, display also unexpected noncanonical functions associated with RNA metabolism in specific subcellular districts (e.g., nucleoli). During the evolution of these key enzymes, the acquisition of unfolded domains significantly amplified the possibility to interact with different partners and substrates, possibly explaining their phylogenetic gain of functions.
  
  
  BACKGROUND
  After nucleolar stress or DNA damage, many DNA repair proteins can freely relocalize from nucleoli to the nucleoplasm. This process may represent a surveillance mechanism to monitor the synthesis and correct assembly of ribosomal units affecting cell cycle progression or inducing p53-mediated apoptosis or senescence.
  
  
  RESULTS
  A paradigm for this kind of regulation is represented by some enzymes of the DNA base excision repair (BER) pathway, such as apurinic/apyrimidinic endonuclease 1 (APE1). In this review, the role of the nucleolus and the noncanonical functions of the APE1 protein are discussed in light of their possible implications in human pathologies.
  
  
  CONCLUSIONS
  A productive cross-talk between DNA repair enzymes and proteins involved in RNA metabolism seems reasonable as the nucleolus is emerging as a dynamic functional hub that coordinates cell growth arrest and DNA repair mechanisms. These findings will drive further analyses on other BER proteins and might imply that nucleic acid processing enzymes are more versatile than originally thought having evolved DNA-targeted functions after a previous life in the early RNA world.
authors.affiliation: Department of Medical and Biological Sciences, University of Udine , Udine, Italy .
authors.forename: Giulia
authors.initials: G
authors.lastname: Antoniali
authors.forename: Lisa
authors.initials: L
authors.lastname: Lirussi
authors.forename: Mattia
authors.initials: M
authors.lastname: Poletto
authors.forename: Gianluca
authors.initials: G
authors.lastname: Tell
mesh_terms: D000818:Animals; D002466:Cell Nucleolus / Q000201:enzymology* / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000502:physiology; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D017434:Protein Structure, Tertiary
chemical_list: D009687:Nuclear Proteins; D000090243:Nucleophosmin; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D045643:DNA Repair Enzymes