Roles for APRIN (PDS5B) in homologous recombination and in ovarian cancer prediction

Nucleic Acids Res. 2016 Dec 15;44(22):10879-10897. doi: 10.1093/nar/gkw921. Epub 2016 Oct 24.

Abstract

APRIN (PDS5 cohesin associated factor B) interacts with both the cohesin complex and the BRCA2 tumor suppressor. How APRIN influences cohesion and DNA repair processes is not well understood. Here, we show that APRIN is recruited to DNA damage sites. We find that APRIN interacts directly with RAD51, PALB2 and BRCA2. APRIN stimulates RAD51-mediated DNA strand invasion. APRIN also binds DNA with an affinity for D-loop structures and single-strand (ss) DNA. APRIN is a new homologous recombination (HR) mediator as it counteracts the RPA inhibitory effect on RAD51 loading to ssDNA. We show that APRIN strongly improves the annealing of complementary-strand DNA and that it can stimulate this process in synergy with BRCA2. Unlike cohesin constituents, its depletion has no impact on class switch recombination, supporting a specific role for this protein in HR. Furthermore, we show that low APRIN expression levels correlate with a better survival in ovarian cancer patients and that APRIN depletion sensitizes cells to the PARP inhibitor Olaparib in xenografted zebrafish. Our findings establish APRIN as an important and specific actor of HR, with cohesin-independent functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / pharmacology
  • BRCA2 Protein / metabolism
  • Benzimidazoles / pharmacology
  • Biomarkers, Tumor / chemistry
  • Biomarkers, Tumor / physiology*
  • Cell Line, Tumor
  • DNA Damage
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / physiology*
  • Drug Resistance, Neoplasm
  • Fanconi Anemia Complementation Group N Protein
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Middle Aged
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / mortality
  • Phthalazines / pharmacology
  • Piperazines / pharmacology
  • Protein Binding
  • Protein Transport
  • ROC Curve
  • Rad51 Recombinase / metabolism
  • Recombinational DNA Repair
  • Squamous Intraepithelial Lesions of the Cervix / diagnosis
  • Squamous Intraepithelial Lesions of the Cervix / drug therapy
  • Squamous Intraepithelial Lesions of the Cervix / metabolism*
  • Squamous Intraepithelial Lesions of the Cervix / mortality
  • Transcription Factors / chemistry
  • Transcription Factors / physiology*
  • Tumor Suppressor Proteins / metabolism
  • Xenograft Model Antitumor Assays
  • Zebrafish

Substances

  • Antineoplastic Agents
  • BRCA2 Protein
  • BRCA2 protein, human
  • Benzimidazoles
  • Biomarkers, Tumor
  • DNA-Binding Proteins
  • Fanconi Anemia Complementation Group N Protein
  • Nuclear Proteins
  • PALB2 protein, human
  • PDS5B protein, human
  • Phthalazines
  • Piperazines
  • Transcription Factors
  • Tumor Suppressor Proteins
  • veliparib
  • RAD51 protein, human
  • Rad51 Recombinase
  • olaparib

Grants and funding