PTIP associates with Artemis to dictate DNA repair pathway choice
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Dec 15, 2014
- Source ID
- 10.1101/gad.252478.114
Entities
People
- Asaithamby Aroumougame
- David Chen
- Jiadong Wang
- Junjie Chen
- Markus Lobrich
- Yujing Li
- Zihua Gong
Organizations
- National Institutes of Health
- The University of Texas MD Anderson Cancer Center
- United States Department of Defense