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Published on: June 26, 2020
The chromatin scaffold protein SAFB1 renders chromatin permissive for DNA damage signaling
Matthias Altmeyer1, Luis Toledo, Thorkell Gudjonsson
1Chromosome Stability and Dynamics Group, Department of Disease Biology, the Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Abstract:
Although the general relevance of chromatin modifications for genotoxic stress signaling, cell-cycle checkpoint activation, and DNA repair is well established, how these modifications reach initial thresholds in order to trigger robust responses remains largely unexplored. Here, we identify the chromatin-associated scaffold attachment factor SAFB1 as a component of the DNA damage response and show that SAFB1 cooperates with histone acetylation to allow for efficient γH2AX spreading and genotoxic stress signaling. SAFB1 undergoes a highly dynamic exchange at damaged chromatin in a poly(ADP-ribose)-polymerase 1- and poly(ADP-ribose)-dependent manner and is required for unperturbed cell-cycle checkpoint activation and guarding cells against replicative stress. Altogether, our data reveal that transient recruitment of an architectural chromatin component is required in order to overcome physiological barriers by making chromatin permissive for DNA damage signaling, whereas the ensuing exclusion of SAFB1 may help prevent excessive signaling.
Insights
The scaffold attachment factor SAFB1 aids DNA damage signaling by making chromatin more accessible. Its dynamic recruitment and exclusion help regulate cell-cycle checkpoints and prevent excessive responses to genotoxic stress.
Area of Science:
- Molecular Biology
- Cell Biology
- Genetics
Background:
- Chromatin modifications are crucial for DNA damage response, cell-cycle checkpoints, and DNA repair.
- The initial mechanisms triggering robust responses to genotoxic stress are not fully understood.
Purpose of the Study:
- To identify novel components of the DNA damage response.
- To elucidate the role of scaffold attachment factor SAFB1 (SAFB1) in genotoxic stress signaling and cell-cycle regulation.
Main Methods:
- Chromatin immunoprecipitation
- Western blotting
- Cell cycle analysis
- Immunofluorescence microscopy
Main Results:
- SAFB1 is identified as a component of the DNA damage response.
- SAFB1 facilitates efficient γH2AX spreading and genotoxic stress signaling in cooperation with histone acetylation.
- SAFB1 exhibits dynamic exchange at damaged chromatin, dependent on poly(ADP-ribose)-polymerase 1 and poly(ADP-ribose).
- SAFB1 is essential for proper cell-cycle checkpoint activation and protection against replicative stress.
Conclusions:
- Transient recruitment of SAFB1 makes chromatin permissive for DNA damage signaling, overcoming physiological barriers.
- The subsequent exclusion of SAFB1 may prevent overactive signaling, highlighting its role in fine-tuning the DNA damage response.
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