Tankyrases Promote Homologous Recombination and Check Point Activation in Response to DSBs

Zita Nagy; Alkmini Kalousi; Audrey Furst; Marc Koch; Benoit Fischer; Evi Soutoglou

doi:10.1371/journal.pgen.1005791

Tankyrases Promote Homologous Recombination and Check Point Activation in Response to DSBs

PLoS Genet. 2016 Feb 4;12(2):e1005791. doi: 10.1371/journal.pgen.1005791. eCollection 2016 Feb.

Authors

Zita Nagy^{1

2

3

4}, Alkmini Kalousi^{1

2

3

4}, Audrey Furst^{1

2

3

4}, Marc Koch^{1

2

3

4}, Benoit Fischer^{1

2

3

4}, Evi Soutoglou^{1

2

3

4}

Affiliations

¹ Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France.
² Institut National de la Santé et de la Recherche Médicale (INSERM), U964, Illkirch, France.
³ Centre National de Recherche Scientifique (CNRS), UMR7104, Illkirch, France.
⁴ Université de Strasbourg, Illkirch, France.

Abstract

DNA lesions are sensed by a network of proteins that trigger the DNA damage response (DDR), a signaling cascade that acts to delay cell cycle progression and initiate DNA repair. The Mediator of DNA damage Checkpoint protein 1 (MDC1) is essential for spreading of the DDR signaling on chromatin surrounding Double Strand Breaks (DSBs) by acting as a scaffold for PI3K kinases and for ubiquitin ligases. MDC1 also plays a role both in Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR) repair pathways. Here we identify two novel binding partners of MDC1, the poly (ADP-ribose) Polymerases (PARPs) TNKS1 and 2. We find that TNKSs are recruited to DNA lesions by MDC1 and regulate DNA end resection and BRCA1A complex stabilization at lesions leading to efficient DSB repair by HR and proper checkpoint activation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism
BRCA1 Protein / genetics
BRCA1 Protein / metabolism
Binding Sites
Cell Cycle Proteins
Cell Line
DNA Breaks, Double-Stranded*
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
Homologous Recombination*
Humans
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Rad51 Recombinase / genetics
Rad51 Recombinase / metabolism
Tankyrases / genetics
Tankyrases / metabolism*
Trans-Activators / genetics
Trans-Activators / metabolism
Ubiquitin-Protein Ligases

Substances

Adaptor Proteins, Signal Transducing
BABAM1 protein, human
BRCA1 Protein
BRCA1 protein, human
Cell Cycle Proteins
DNA-Binding Proteins
MDC1 protein, human
Nuclear Proteins
RNF8 protein, human
Trans-Activators
Ubiquitin-Protein Ligases
TNKS2 protein, human
Tankyrases
TNKS protein, human
RAD51 protein, human
Rad51 Recombinase

Grants and funding

This project was funded by the Human Frontiers Science program (HFSP CDA), Fondation pour la Recherche Médicale (FRM), the Agence nationale de la recherché (program Blanc), the Centre National de la Reserache Scientifique (CNRS, ATIP), the Institut national du cancer (INCA libre) and the European FP7 framework (Marie Curie Reintegration grant), the Fondation Schlumberger (FSER) and the EMBO Young Investigator Program (EMBO YIP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.