PTIP associates with Artemis to dictate DNA repair pathway choice

Genes Dev. 2014 Dec 15;28(24):2693-8. doi: 10.1101/gad.252478.114.

Abstract

PARP inhibitors (PARPis) are being used in patients with BRCA1/2 mutations. However, doubly deficient BRCA1(-/-)53BP1(-/-) cells or tumors become resistant to PARPis. Since 53BP1 or its known downstream effectors, PTIP and RIF1 (RAP1-interacting factor 1 homolog), lack enzymatic activities directly implicated in DNA repair, we decided to further explore the 53BP1-dependent pathway. In this study, we uncovered a nuclease, Artemis, as a PTIP-binding protein. Loss of Artemis restores PARPi resistance in BRCA1-deficient cells. Collectively, our data demonstrate that Artemis is the major downstream effector of the 53BP1 pathway, which prevents end resection and promotes nonhomologous end-joining and therefore directly competes with the homologous recombination repair pathway.

Keywords: 53BP1; Artemis; BRCA1; DNA repair; PARP inhibition; PTIP.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • DNA Repair / genetics
  • DNA Repair / physiology*
  • DNA-Binding Proteins
  • Endonucleases
  • Gene Knockout Techniques
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding
  • Protein Structure, Tertiary
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • PAXIP1 protein, human
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • DCLRE1C protein, human
  • Endonucleases