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PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair
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PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair
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Journal Article
PARylation of GCN5 by PARP1 mediates its recruitment to DSBs and facilitates both HR and NHEJ Repair
2024
Overview
Efficient DNA double strand break (DSB) repair is necessary for genomic stability and determines efficacy of DNA damaging cancer therapeutics. Spatiotemporal dynamics and post-translational modifications of repair proteins at DSBs dictate repair efficacy. Here, we identified a non-canonical function of GCN5 in regulating both HR and NHEJ repair post genotoxic stress. Mechanistically, genotoxic stress induced GCN5 recruitment to DSBs. GCN5 PARylation by PARP1 was essential for its recruitment, acetyltransferase activity and DSB repair function. Liquid chromatography-mass spectrometry (LC–MS) identified DNA-PKcs as part of GCN5 interactome.
In-vitro
acetyltransferase assays revealed that GCN5 acetylates DNA-PKcs at K3241 residue, a prerequisite for DNA-PKcs S2056 phosphorylation and DSB recruitment. Alongside, ChIP-qPCR revealed GCN5 mediates transcription of
PRKDC
via H3K27Ac acetylation in its promoter region (− 710 to − 554). Genetic perturbation of GCN5 also decreased
CHEK1, NBN1, TP53BP1, POL-L
transcription and abrogated ATM, BRCA1 activation. Accordingly, GCN5 loss led to persistent ɣ-H2AX foci formation, compromised in-vivo HR-NHEJ and caused GBM radio-sensitization. Importantly, PARP1 inhibition phenocopied GCN5 loss. Together, this study identifies an untraversed DSB repair function of GCN5 and provides mechanistic insights into transcriptional as well as post-translational regulation of pivotal HR-NHEJ factors. Alongside, it highlights the translational importance of PARP1-GCN5 axis in mediating GBM radio-resistance.
Publisher
Springer International Publishing,Springer Nature B.V
Subject
/ Animals
/ Biomedical and Life Sciences
/ DNA
/ DNA-Activated Protein Kinase - genetics
/ DNA-Activated Protein Kinase - metabolism
/ DNA-dependent protein kinase
/ genomics
/ Humans
/ Kinases
/ Leukemia
/ Mice
/ mutagens
/ Nuclear Proteins - metabolism
/ p300-CBP Transcription Factors - genetics
/ p300-CBP Transcription Factors - metabolism
/ Poly (ADP-Ribose) Polymerase-1 - genetics
/ Poly (ADP-Ribose) Polymerase-1 - metabolism
/ Protein Processing, Post-Translational
/ Proteins
/ Yeast
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