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Published on: June 26, 2020
The nuclear oncogene SET controls DNA repair by KAP1 and HP1 retention to chromatin
Alkmini Kalousi1, Anne-Sophie Hoffbeck1, Platonas N Selemenakis2
1Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 Centre National de la Recherche Scientifique (CNRS), UdS, INSERM U964, BP 10142, 67404 Illkirch Cedex, Strasbourg, France.
Abstract:
Cells experience damage from exogenous and endogenous sources that endanger genome stability. Several cellular pathways have evolved to detect DNA damage and mediate its repair. Although many proteins have been implicated in these processes, only recent studies have revealed how they operate in the context of high-ordered chromatin structure. Here, we identify the nuclear oncogene SET (I2PP2A) as a modulator of DNA damage response (DDR) and repair in chromatin surrounding double-strand breaks (DSBs). We demonstrate that depletion of SET increases DDR and survival in the presence of radiomimetic drugs, while overexpression of SET impairs DDR and homologous recombination (HR)-mediated DNA repair. SET interacts with the Kruppel-associated box (KRAB)-associated co-repressor KAP1, and its overexpression results in the sustained retention of KAP1 and Heterochromatin protein 1 (HP1) on chromatin. Our results are consistent with a model in which SET-mediated chromatin compaction triggers an inhibition of DNA end resection and HR.
Insights
The nuclear oncogene SET (I2PP2A) regulates DNA damage response and repair. SET overexpression compacts chromatin, inhibiting DNA repair pathways like homologous recombination (HR).
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Cells possess pathways to detect and repair DNA damage, crucial for genome stability.
- Understanding protein roles within chromatin structure during DNA repair is an evolving area of research.
Purpose of the Study:
- To investigate the role of the nuclear oncogene SET (I2PP2A) in the DNA damage response (DDR) and repair within chromatin.
Main Methods:
- Depletion and overexpression of SET in cells.
- Assessing DNA damage response and survival under genotoxic stress.
- Analyzing protein-chromatin interactions, including KAP1 and HP1 retention.
Main Results:
- SET depletion enhanced DDR and cell survival against radiomimetic drugs.
- SET overexpression impaired DDR and homologous recombination (HR)-mediated repair.
- SET interacts with KAP1, and its overexpression leads to sustained KAP1 and HP1 on chromatin.
Conclusions:
- SET acts as a modulator of DDR and DNA repair.
- SET-mediated chromatin compaction inhibits DNA end resection and HR.
- Findings suggest a model where SET influences chromatin structure to regulate DNA repair efficiency.
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