ATM and DNA-PKcs make a complementary couple in DNA double strand break repair

Martı́n, Marga; Terradas, Mariona; Tusell, Laura; Genescà, Anna

doi:10.1016/j.mrrev.2011.12.006

Cited by 20 publications

(11 citation statements)

References 92 publications

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“…Upon DNA damage, DNA-PKcs is recruited to the damage foci together with the regulatory subunits Ku70/Ku80. DNA-PKcs or ataxia-telangiectasia-mutated (ATM) then phosphorylates S139 in H2Ax, creating γH2Ax (Martin et al, 2012). We therefore used γH2Ax as a hallmark of DSB (Dinant et al, 2008) and examined whether depletion of HP1β in U2OS cells had an effect on γH2Ax prior to or following etoposide treatment.…”

Section: Resultsmentioning

confidence: 99%

A Method for Systematic Mapping of Protein Lysine Methylation Identifies Functions for HP1β in DNA Damage Response

et al. 2013

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SUMMARY Lysine methylation occurs on both histone and non-histone proteins. However, our knowledge on the prevalence and function of non-histone protein methylation is poor. We describe here an approach that combines peptide array, bioinformatic and mass spectrometric analyses to systematically identify lysine methylation sites in proteins and methyllysine-mediated protein-protein interactions. We demonstrate the utility of this approach by identifying a methyllysine-driven interactome of the heterochromatin protein (HP) 1β and uncovering, simultaneously, numerous methyllysine sites on non-histone proteins. The HP1β interactome is enriched with proteins involved in DNA damage repair and RNA splicing. We showed that lysine methylation played a pivotal role in the function of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and its interaction with HP1β during DNA damage response. Moreover, by combining heavy methyl SILAC with Multiple Reaction Monitoring (MRM) mass spectrometry (MS), we showed that lysine methylation underwent widespread and large changes in response to DNA damage. Our work indicates that lysine methylation is a highly dynamic post-translational modification occurring frequently on non-histone proteins and that the approach presented herein may be extended to many methyllysine-binding modules to systematically uncover lysine methylation events in the cell.

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Section: Resultsmentioning

confidence: 99%

A Method for Systematic Mapping of Protein Lysine Methylation Identifies Functions for HP1β in DNA Damage Response

et al. 2013

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“…DNA-PKcs has redundant functions with ATM and Cernunnos during DNA repair (49)(50)(51)(52). Double deficiency in DNA-PKcs and ATM or Cernunnos results in more severe defects in both CSR (17,51) and V(D)J recombination (51) than does single deficiency in DNA-PKcs, ATM, or Cernunnos in mice.…”

Section: Discussionmentioning

confidence: 99%

DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells

Björkman

Felgentreff

et al. 2015

The Journal of Immunology

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Nonhomologous end-joining (NHEJ) is one of the major DNA double-strand break repair pathways in mammalian cells and is required for both V(D)J recombination and class switch recombination (CSR), two Ig gene–diversification processes occurring during B cell development. DNA-dependent protein kinase, catalytic subunit (DNA-PKcs) is a component of the classical NHEJ machinery and has a critical function during V(D)J recombination. However, its role in CSR has been controversial. In this study, we examined the pattern of recombination junctions from in vivo–switched B cells from two DNA-PKcs–deficient patients. One of them harbored mutations that did not affect DNA-PKcs kinase activity but caused impaired Artemis activation; the second patient had mutations resulting in diminished DNA-PKcs protein expression and kinase activity. These results were compared with those from DNA-PKcs–deficient mouse B cells. A shift toward the microhomology-based alternative end-joining at the recombination junctions was observed in both human and mouse B cells, suggesting that the classical NHEJ pathway is impaired during CSR when DNA-PKcs is defective. Furthermore, cells from the second patient showed additional or more severe alterations in CSR and/or NHEJ, which may suggest that DNA-PKcs and/or its kinase activity have additional, Artemis-independent functions during these processes.

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“…Treatment with camptothecin, a topoisomerase 1 inhibitor, induces DSB during S-phase, thereby promoting apoptosis via caspases 3 and 9. Furthermore, ATM and DNA-PKcs, which act complementary and are necessary to avoid errors during DNA repair (Martin et al 2012), are translocated to sites of DSB and activate downstream signaling cascades (γH2AX foci, p53 phosphorylation and stabilization)-indicating functional PI3KK pathways (Garcia et al 2014).…”

Section: Regulation Of Apoptosis In Hesc and Hipscmentioning

confidence: 99%

Full biological characterization of human pluripotent stem cells will open the door to translational research

et al. 2016

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Since the discovery of human embryonic stem cells (hESC) and human-induced pluripotent stem cells (hiPSC), great hopes were held for their therapeutic application including disease modeling, drug discovery screenings, toxicological screenings and regenerative therapy. hESC and hiPSC have the advantage of indefinite self-renewal, thereby generating an inexhaustible pool of cells with, e.g., specific genotype for developing putative treatments; they can differentiate into derivatives of all three germ layers enabling autologous transplantation, and via donor-selection they can express various genotypes of interest for better disease modeling. Furthermore, drug screenings and toxicological screenings in hESC and hiPSC are more pertinent to identify drugs or chemical compounds that are harmful for human, than a mouse model could predict. Despite continuing research in the wide field of therapeutic applications, further understanding of the underlying basic mechanisms of stem cell function is necessary. Here, we summarize current knowledge concerning pluripotency, self-renewal, apoptosis, motility, epithelial-to-mesenchymal transition and differentiation of pluripotent stem cells.

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ATM and DNA-PKcs make a complementary couple in DNA double strand break repair

Cited by 20 publications

References 92 publications

A Method for Systematic Mapping of Protein Lysine Methylation Identifies Functions for HP1β in DNA Damage Response

A Method for Systematic Mapping of Protein Lysine Methylation Identifies Functions for HP1β in DNA Damage Response

DNA-PKcs Is Involved in Ig Class Switch Recombination in Human B Cells

Full biological characterization of human pluripotent stem cells will open the door to translational research

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