DNA-PK, ATM and ATR collaboratively regulate p53–RPA interaction to facilitate homologous recombination DNA repair

Serrano, Moises A.; Li, Zhengke; Dangeti, Mohan; Musich, Phillip R.; Patrick, Steve M.; Roginskaya, Marina; Cartwright, Brian M.; Zou, Yue

doi:10.1038/onc.2012.257

Cited by 92 publications

(85 citation statements)

References 60 publications

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“…Such competition was also reported between p53 and a phosphomimetic peptide of the RPA32 N-terminus [37]. In agreement with this, hyperphosphorylated RPA32 shows an abrogated interaction with p53 in an ATR-, ATM-and DNA-PK-regulated manner [115,116]. It has also been reported that CPT treatment leads to the dissociation of an RPA-DNA-PK complex concomitantly with RPA phosphorylation and a decrease in DNA synthesis [117].…”

Section: Rpa Phosphorylation and Protein-protein Interactionssupporting

confidence: 63%

RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response

2014

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The Replication Protein A (RPA) complex is an essential regulator of eukaryotic DNA metabolism. RPA avidly binds to single-stranded DNA (ssDNA) through multiple oligonucleotide/oligosaccharide-binding folds and coordinates the recruitment and exchange of genome maintenance factors to regulate DNA replication, recombination and repair. The RPA-ssDNA platform also constitutes a key physiological signal which activates the master ATR kinase to protect and repair stalled or collapsed replication forks during replication stress. In recent years, the RPA complex has emerged as a key target and an important regulator of post-translational modifications in response to DNA damage, which is critical for its genome guardian functions. Phosphorylation and SUMOylation of the RPA complex, and more recently RPA-regulated ubiquitination, have all been shown to control specific aspects of DNA damage signaling and repair by modulating the interactions between RPA and its partners. Here, we review our current understanding of the critical functions of the RPA-ssDNA platform in the maintenance of genome stability and its regulation through an elaborate network of covalent modifications.

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Section: Rpa Phosphorylation and Protein-protein Interactionssupporting

confidence: 63%

RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response

2014

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“…all 3 patient cell lines a marked increase in phosphorylation of p53 at Ser37 ( Figure 8D), a target of the ATM/ATR DDR kinases (38). Collectively, these data support an ATR-X disease model whereby rapid myoblast proliferation results in the accumulation of DNA damage during replication, which in turn activates the p53-ATM DDR pathway and increases the frequency of genomic instability.…”

Section: Figuresupporting

confidence: 54%

Compromised genomic integrity impedes muscle growth after Atrx inactivation

Huh¹,

O’Dea²,

Ouazia³

et al. 2012

J. Clin. Invest.

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ATR-X syndrome is a severe intellectual disability disorder caused by mutations in the ATRX gene. Many ancillary clinical features are attributed to CNS deficiencies, yet most patients have muscle hypotonia, delayed ambulation, or kyphosis, pointing to an underlying skeletal muscle defect. Here, we identified a cell-intrinsic requirement for Atrx in postnatal muscle growth and regeneration in mice. Mice with skeletal muscle-specific Atrx conditional knockout (Atrx cKO mice) were viable, but by 3 weeks of age presented hallmarks of underdeveloped musculature, including kyphosis, 20% reduction in body mass, and 34% reduction in muscle fiber caliber. Atrx cKO mice also demonstrated a marked regeneration deficit that was not due to fewer resident satellite cells or their inability to terminally differentiate. However, activation of Atrx-null satellite cells from isolated muscle fibers resulted in a 9-fold reduction in myoblast expansion, caused by delayed progression through mid to late S phase. While in S phase, Atrx colocalized specifically to late-replicating chromatin, and its loss resulted in rampant signs of genomic instability. These observations support a model in which Atrx maintains chromatin integrity during the rapid developmental growth of a tissue.

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“…DNA-PKcs promotes NHEJ while suppressing homologous recombination 20 and facilitates repair of genotoxic and replication stress associated damage via phosphorylation of the single-stranded DNA-binding protein replication protein A 2. 21 Similar to MSI1, DNA-PKcs gene expression is increased on radiation (Supplemental Figure S2B). Moreover, we observed a replication protein A 2 hyperphosphorylation pattern after MSI1 overexpression in U251 cells ( Figure 3A) concordant with the induction of DNA damage response in a DNA-PKedependent manner.…”

Section: Msi1 Targets Dna-pkcsmentioning

confidence: 94%

Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

Araújo

Gorthi

Silva

et al. 2016

The American Journal of Pathology

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The conserved RNA-binding protein Musashi1 (MSI1) has been characterized as a stem cell marker, controlling the balance between self-renewal and differentiation and as a key oncogenic factor in numerous solid tumors, including glioblastoma. To explore the potential use of MSI1 targeting in therapy, we studied MSI1 in the context of radiation sensitivity. Knockdown of MSI1 led to a decrease in cell survival and an increase in DNA damage compared to control in cells treated with ionizing radiation. We subsequently examined mechanisms of double-strand break repair and found that loss of MSI1 reduces the frequency of nonhomologous end-joining. This phenomenon could be attributed to the decreased expression of DNAeprotein kinase catalytic subunit, which we have previously identified as a target of MSI1. Collectively, our results suggest a role for MSI1 in double-strand break repair and that its inhibition may enhance the effect of radiotherapy. Glioblastoma multiforme is the most aggressive form of glioma and is the most common among primary brain tumors. The current standard of care for newly diagnosed glioblastoma is surgical resection, followed by concurrent temozolomide and radiotherapy, then by maintenance chemotherapy with temozolomide. Unfortunately, this route offers a median survival of only approximately 14 months.

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DNA-PK, ATM and ATR collaboratively regulate p53–RPA interaction to facilitate homologous recombination DNA repair

Cited by 92 publications

References 60 publications

RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response

RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response

Compromised genomic integrity impedes muscle growth after Atrx inactivation

Musashi1 Impacts Radio-Resistance in Glioblastoma by Controlling DNA-Protein Kinase Catalytic Subunit

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