GSE1 links the HDAC1/CoREST co-repressor complex to DNA damage

Area of Science:

• Molecular Biology
• Cellular Biology
• Epigenetics

Background:

• Post-translational modifications of histones regulate the DNA damage response (DDR).
• Genetic Suppressor Element 1 (GSE1) is implicated in cancer progression.

Purpose of the Study:

• To investigate the role of GSE1 in the DNA damage response.
• To elucidate the molecular mechanisms by which GSE1 influences DDR and histone modifications.

Main Methods:

• Affinity purification mass spectrometry (AP-MS) to identify protein complexes.
• Phosphorylome analysis to assess global phosphorylation changes.
• Western blotting and immunofluorescence to detect protein modifications and signaling.

Main Results:

• GSE1 forms a complex with the HDAC1/CoREST co-repressor complex.
• Loss of GSE1 impairs DDR, ATR signaling, and γH2AX formation.
• GSE1 is essential for USP22 binding to CoREST and H2B K120 deubiquitination during DDR.
• The USP22-GSE1-CoREST complex acts as a multi-enzymatic eraser in DDR.

Conclusions:

• GSE1 plays a critical role in DNA damage sensing and response pathways.
• GSE1 is essential for regulating histone modifications, specifically H2B deubiquitination, via the USP22-GSE1-CoREST complex.
• These findings highlight the medical relevance of GSE1 in cancer biology and DDR.