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DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect [RNA-Seq]

ABSTRACT: DNA damage repair and transcription are antagonistic cellular processes that require precise spatiotemporal coordination to maintain genomic integrity. Transcriptional silencing at DSB sites is essential for efficient repair, mediated through localized histone modifications and direct inhibition of RNA polymerase II (Pol II). However, the role of transcriptional activators in coordinating DSB repair with transcriptional silencing remains elusive. Here, we identify the transcriptional coactivator CRTC2 as a key coordinator of DNA repair and transcriptional regulation. We demonstrate that CRTC2 promotes canonical non-homologous end joining (c-NHEJ) both in vitro and in vivo. Mechanistically, PARP1 activation recruits CRTC2 to DNA breaks, where it facilitates DNA-PKcs recruitment and assembly of the DNA-PK holoenzyme, thereby driving c-NHEJ. DNA-PK–mediated phosphorylation of CRTC2 at Ser433 dissociates it from transcriptional complexes, suppressing target gene transcription, and promoting its incorporation into DNA repair complexes. Thus, establishing a positive feedback loop that enhances NHEJ efficiency. CRTC2 loss radiosensitizes cancer cells, potentiates irradiation-induced cGAS–STING activation, promotes cytotoxic CD8⁺ T cell infiltration, and enhances the abscopal effect. Furthermore, AAV8-mediated targeting of CRTC2 sensitizes tumors to radioimmunotherapy. Our results reveal CRTC2 as bifunctional nodal effector coupling transcriptional silencing to DNA repair and propose its inhibition as a promising strategy for radioimmunotherapy sensitization in resistant malignancies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE306599 | GEO | 2026/04/20

REPOSITORIES: GEO

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DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect

Project description:DNA damage repair and transcription are antagonistic cellular processes that require precise spatiotemporal coordination to maintain genomic integrity. Transcriptional silencing at DSB sites is essential for efficient repair, mediated through localized histone modifications and direct inhibition of RNA polymerase II (Pol II). However, the role of transcriptional activators in coordinating DSB repair with transcriptional silencing remains elusive. Here, we identify the transcriptional coactivator CRTC2 as a key coordinator of DNA repair and transcriptional regulation. We demonstrate that CRTC2 promotes canonical non-homologous end joining (c-NHEJ) both in vitro and in vivo. Mechanistically, PARP1 activation recruits CRTC2 to DNA breaks, where it facilitates DNA-PKcs recruitment and assembly of the DNA-PK holoenzyme, thereby driving c-NHEJ. DNA-PK–mediated phosphorylation of CRTC2 at Ser433 dissociates it from transcriptional complexes, suppressing target gene transcription, and promoting its incorporation into DNA repair complexes. Thus, establishing a positive feedback loop that enhances NHEJ efficiency. CRTC2 loss radiosensitizes cancer cells, potentiates irradiation-induced cGAS–STING activation, promotes cytotoxic CD8⁺ T cell infiltration, and enhances the abscopal effect. Furthermore, AAV8-mediated targeting of CRTC2 sensitizes tumors to radioimmunotherapy. Our results reveal CRTC2 as bifunctional nodal effector coupling transcriptional silencing to DNA repair and propose its inhibition as a promising strategy for radioimmunotherapy sensitization in resistant malignancies.

2026-04-20 | GSE307028 | GEO

DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect [CUT&Tag]

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Homeodomain-containing protein PRRX1 senses DNA double-strand breaks and anchors the Ku heterodimers to promote non-homologous end-joining

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DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect

Project description:DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect

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DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect [CUT&Tag]

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DNA-PK Mediated CRTC2 Phosphorylation Promotes CRTC2 Relocation from Transcription to Repair Complexes Enhancing NHEJ and Suppressing Abscopal Effect [RNA-Seq]

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Transcriptome data for HEK293T cells depleted of one subunit of DNA-PK complex: Ku70, Ku80 or DNA-PKcs.

Project description:DNA-PK is a heterotrimeric complex that consists of Ku70 (XRCC6), Ku80 (XRCC5) and DNA-PKcs (PRKDC) subunits. DNA-PK complex is a major player in DNA double strand break (DSB) repair via non-homologous end joining pathway. This process requires all of DNA-PK subunits. Ku70/Ku80 heterodimers firstly bind to DNA-ends at DSB, that increase affinity of DNA-PKcs to DNA-ends. Recruitment of DNA-PKcs subunit to DSB leads to phosphorylation events near DSB, recruitment of another NHEJ-related genes that restore DNA integrity. However, today a lot of evidence demonstrate participation of DNA-PK components in other cellular process, e.g. cytosolic DNA sensing, apoptosis regulation, cellular movement and adhesion. It is important to note that not all subunits of DNA-PK complex are necessary for these process. This demonstrate the independent functions of DNA-PK subunits. Here we for the first time using NGS-sequencing analyzed the transcriptional changes in HEK293T cells under depletion of Ku70, Ku80 or DNA-PKcs to characterize the independent functions of each subunit.

2021-07-23 | GSE180581 | GEO

Ubiquitin ligase WWP2 targets RNA polymerase II in a DNA-PK-dependent transcription shutoff circuitry for DNA repair

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2019-03-29 | PXD012606 | Pride

DNA-PK Promotes DNA End Resection at DNA Double Strand Breaks in G0 cells [ChIP-Seq]

Project description:DNA double-strand break (DSB) repair by homologous recombination is confined to the S and G2 phases of the cell cycle partly due to 53BP1 antagonizing DNA end resection in G1 phase and non-cycling quiescent (G0) cells where DSBs must be repaired by non-homologous end joining (NHEJ). Unexpectedly, we uncovered extensive MRE11- and CtIP-dependent DNA end resection at DSBs in G0 mammalian cells. A whole genome CRISPR/Cas9 screen revealed the DNA-dependent kinase (DNA-PK) complex as a key factor in promoting DNA end resection in G0 cells. In agreement, depletion of FBXL12, which promotes ubiquitylation and removal of the KU70/KU80 subunits of DNA-PK from DSBs, promotes even more extensive resection in G0 cells. In contrast, a requirement for DNA-PK in promoting DNA end resection in cycling cells at the G1 or G2 phase cells was not observed. Our findings establish that DNA-PK uniquely promotes DNA end resection in G0, but not in G1 or G2 phase cells, and has important implications for DNA DSB repair in quiescent cells.

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