Discordance between phosphorylation and recruitment of 53BP1 in response to DNA double-strand breaks

Harding, Shane M.; Bristow, Robert G.

doi:10.4161/cc.19824

Cited by 48 publications

(46 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It accumulates on the methylated H4K20 dock at the DNA damage site and co-localizes with γH2AX to form the DNA repair complex. [27][28][29] However, in our study, when 53BP1 expression was decreased after MBTD1 or Pr-Set7 depletion, increased γH2AX foci were formed. We assumed that depletion of MBTD1 and Pr-Set7 would cause abrogation of H4K20me1, the substrate of H4K20me2 and H4K20me3 and binding sites of 53BP1, 30,31 thus resulting in decreased expression of 53BP1.…”

Section: Discussioncontrasting

confidence: 70%

MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation

Luo

Zhang

et al. 2013

Cell Cycle

View full text Add to dashboard Cite

Section: Discussioncontrasting

confidence: 70%

MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation

Luo

Zhang

et al. 2013

Cell Cycle

View full text Add to dashboard Cite

“…These results indicate that by interacting with DNA-PKcs TMPRSS2-ERG does indeed inhibit DNA-PKcs Thr2609 and Ser2056 auto-phosphorylation required for its function. Finally, we and others have shown that Ser1778 is a 53BP1 C-terminal phosphorylation target of DNA-PKcs (37, 38) that contributes significantly to DNA repair after IR (39). Ser1778 53BP1 foci were also absent in PC3 cells expressing TMPRSS2-ERG (Fig.…”

Section: Resultsmentioning

confidence: 81%

“…As a previous report suggested that DNA-PKcs binds to the ERG fusion gene product (12), this interaction might hinder the recruitment or retention of other c-NHEJ factors. We show that DNA-PKcs activity is suppressed in the presence of TMPRSS2-ERG, as indicated by the absence of foci of Thr2609 and Ser2056 DNA-PKcs and a critical DNA-PKcs substrate, Ser1778-53BP1 (37), as well as limited DNA-PKcs auto-phosphorylation. The higher levels of chromatin-associated DNA-PKCs in the presence of TMPRSS2-ERG suggests that its dissociation from DSBs was impaired, consistent with its defective autophosphorylation.…”

Section: Discussionmentioning

confidence: 84%

See 1 more Smart Citation

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Chatterjee

Choudhary

Alswillah

et al. 2015

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Exposure to genotoxic agents, such as ionizing radiation (IR) produces DNA damage leading to DNA double-strand breaks (DSBs); IR toxicity is augmented when the DNA repair is impaired. We reported that radiosensitization by a PARP inhibitor (PARPi) was highly prominent in prostate cancer (PCa) cells expressing the TMPRSS2-ERG gene fusion protein. Here, we show that TMPRSS2-ERG blocks non-homologous end-joining (NHEJ) DNA repair by inhibiting DNA-PKcs. VCaP cells, which harbor TMPRSS2-ERG and PC3 cells that stably express it displayed γH2AX and 53BP1 foci constitutively, indicating persistent DNA damage that was absent if TMPRSS2-ERG was depleted by siRNA in VCaP cells. The extent of DNA damage was enhanced and associated with TMPRSS2-ERG’s ability to inhibit DNA-PKcs function, as indicated by its own phosphorylation (Thr2609, Ser2056) and that of its substrate, Ser1778-53BP1. DNA-PKcs deficiency caused by TMPRSS2-ERG destabilized critical NHEJ components on chromatin. Thus, XRCC4 was not recruited to chromatin, with retention of other NHEJ core factors being reduced. DNA-PKcs autophosphorylation was restored to the level of parental cells when TMPRSS2-ERG was depleted by siRNA. Following IR, TMPRSS2-ERG-expressing PC3 cells had elevated Rad51 foci and homologous recombination (HR) activity, indicating that HR compensated for defective NHEJ in these cells, hence addressing why TMPRSS2-ERG alone did not lead to radiosensitization. However, the presence of TMPRSS2-ERG, by inhibiting NHEJ DNA repair, enhanced PARPi-mediated radiosensitization. IR in combination with PARPi resulted in enhanced DNA damage in TMPRSS2-ERG-expressing cells. Thus, by inhibiting NHEJ, TMPRSS2-ERG provides a synthetic lethal interaction with PARPi in PCa patients expressing TMPRSS2-ERG.

show abstract

“…Cells were seeded at ~2×10^5 cells per well of a 6-well plate, treated 24h after seeding with IR and the indicated agents, and 6 days later were fixed and stained for SA-βGal as described 33 . Three technical replicates were performed within at least 2 independent biological experiments.…”

Section: Methodsmentioning

confidence: 99%

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Harding

Benci

Irianto

et al. 2017

Nature

Self Cite

1,186

780

View full text Add to dashboard Cite

Inflammatory gene expression following genotoxic cancer therapy is well documented, yet the events underlying its induction remain poorly understood. Inflammatory cytokines modify the tumor microenvironment by recruiting immune cells and are critical for both local and systemic (abscopal) tumor responses to radiotherapy1. An enigmatic feature of this phenomenon is its delayed onset (days), in contrast to the acute DNA damage responses that occur in minutes to hours. Such dichotomous kinetics implicate additional rate limiting steps that are essential for DNA-damage induced inflammation. Here, we show that cell cycle progression through mitosis following DNA double-strand breaks (DSBs) leads to the formation of micronuclei, which precede activation of inflammatory signaling and are a repository for the pattern recognition receptor cGAS. Inhibiting progression through mitosis or loss of pattern recognition by cGAS-STING impaired interferon signaling. Moreover, STING loss prevented the regression of abscopal tumors in the context of ionizing radiation and immune checkpoint blockade in vivo. These findings implicate temporal modulation of the cell cycle as an important consideration in the context of therapeutic strategies that combine genotoxic agents with immune checkpoint blockade.

show abstract

Discordance between phosphorylation and recruitment of 53BP1 in response to DNA double-strand breaks

Cited by 48 publications

References 58 publications

MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation

MBTD1 is associated with Pr-Set7 to stabilize H4K20me1 in mouse oocyte meiotic maturation

The TMPRSS2–ERG Gene Fusion Blocks XRCC4-Mediated Nonhomologous End-Joining Repair and Radiosensitizes Prostate Cancer Cells to PARP Inhibition

Mitotic progression following DNA damage enables pattern recognition within micronuclei

Contact Info

Product

Resources

About