Unknown

Dataset Information

0

DNA double-strand break repair pathway choice is directed by distinct MRE11 nuclease activities.


ABSTRACT: MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following radiation exposure. While nuclease inhibition impairs radiation-induced replication protein A (RPA) chromatin binding, suggesting diminished resection, the inhibitors surprisingly direct different repair outcomes. Endonuclease inhibition promotes NHEJ in lieu of HR, while exonuclease inhibition confers a repair defect. Collectively, the results describe nuclease-specific MRE11 inhibitors, define distinct nuclease roles in DSB repair, and support a mechanism whereby MRE11 endonuclease initiates resection, thereby licensing HR followed by MRE11 exonuclease and EXO1/BLM bidirectional resection toward and away from the DNA end, which commits to HR.

SUBMITTER: Shibata A 

PROVIDER: S-EPMC3909494 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

altmetric image

Publications


MRE11 within the MRE11-RAD50-NBS1 (MRN) complex acts in DNA double-strand break repair (DSBR), detection, and signaling; yet, how its endo- and exonuclease activities regulate DSBR by nonhomologous end-joining (NHEJ) versus homologous recombination (HR) remains enigmatic. Here, we employed structure-based design with a focused chemical library to discover specific MRE11 endo- or exonuclease inhibitors. With these inhibitors, we examined repair pathway choice at DSBs generated in G2 following rad  ...[more]

Similar Datasets

| S-EPMC2681233 | biostudies-literature
| S-EPMC9061753 | biostudies-literature
| S-EPMC3956201 | biostudies-other
| S-EPMC3272152 | biostudies-literature
| S-EPMC3796453 | biostudies-literature
| S-EPMC8985095 | biostudies-literature
2021-04-13 | GSE154729 | GEO
| S-EPMC8198441 | biostudies-literature
| S-EPMC3061033 | biostudies-literature
| S-EPMC3526295 | biostudies-literature