Ziv Y, Bielopolski D, Galanty Y, Lukas C, Taya Y, Schultz DC et al.. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol 8: 870-876

The David and Inez Myers Laboratory for Genetic Research, Department of Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
Nature Cell Biology (Impact Factor: 19.68). 09/2006; 8(8):870-6. DOI: 10.1038/ncb1446
Source: PubMed


The cellular DNA-damage response is a signaling network that is vigorously activated by cytotoxic DNA lesions, such as double-strand breaks (DSBs). The DSB response is mobilized by the nuclear protein kinase ATM, which modulates this process by phosphorylating key players in these pathways. A long-standing question in this field is whether DSB formation affects chromatin condensation. Here, we show that DSB formation is followed by ATM-dependent chromatin relaxation. ATM's effector in this pathway is the protein KRAB-associated protein (KAP-1, also known as TIF1beta, KRIP-1 or TRIM28), previously known as a corepressor of gene transcription. In response to DSB induction, KAP-1 is phosphorylated in an ATM-dependent manner on Ser 824. KAP-1 is phosphorylated exclusively at the damage sites, from which phosphorylated KAP-1 spreads rapidly throughout the chromatin. Ablation of the phosphorylation site of KAP-1 leads to loss of DSB-induced chromatin decondensation and renders the cells hypersensitive to DSB-inducing agents. Knocking down KAP-1, or mimicking a constitutive phosphorylation of this protein, leads to constitutive chromatin relaxation. These results suggest that chromatin relaxation is a fundamental pathway in the DNA-damage response and identify its primary mediators.

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    • "In our work, we suggest that LMTK3 specifically interacts with PP1a, which suppresses KAP1 phosphorylation at LMTK3-chromatin associated regions, thereby maintaining the co-repressor function of this complex. In addition, KAP1 phosphorylation is a DNA damage marker (White et al., 2006; Ziv et al., 2006). Our results show that KAP1 phosphorylation is suppressed during doxorubicin treatment when LMTK3 is overexpressed, which suggests that LMTK3 abundance might delay the induction of DNA damage upon doxorubicin treatment. "
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    ABSTRACT: LMTK3 is an oncogenic receptor tyrosine kinase (RTK) implicated in various types of cancer, including breast, lung, gastric, and colorectal cancer. It is local- izedindifferentcellularcompartments,butitsnuclear functionhasnotbeeninvestigatedsofar.Wemapped LMTK3 binding across the genome using ChIP-seq and found that LMTK3 binding events are corre- lated with repressive chromatin markers. We further identified KRAB-associated protein 1 (KAP1) as a binding partner of LMTK3. The LMTK3/KAP1 interac- tion is stabilized by PP1 a , which suppresses KAP1 phosphorylation specifically at LMTK3-associated chromatin regions, inducing chromatin condensation and resulting in transcriptional repression of LMTK3- bound tumor suppressor-like genes. Furthermore, LMTK3 functions at distal regions in tethering the chromatin to the nuclear periphery, resulting in H3K9me3 modification and gene silencing. In sum- mary, we propose a model where a scaffolding func- tion of nuclear LMTK3 promotes cancer progression through chromatin remodeling.
    Full-text · Article · Aug 2015 · Cell Reports
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    • "Besides, Martínez- López and co-workers found a correspondence in the frequency of chromosomal aberrations between the euchromatic short arm and heterochromatic long arm of the X chromosome after etoposide treatment [16]. Even though various studies have suggested that chromatin architecture strongly influences, both, DNA damage induction and its repair, as well as ATM mediated signalling modifies chromatin structure [17] [18], at present, there are not conclusive data on radiosensitivity of structurally and functionally different chromatin domains. "
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    ABSTRACT: At present, a lot is known about biochemical aspects of double strand breaks (DBS) repair but how chromatin structure affects this process and the sensitivity of DNA to DSB induction is still an unresolved question. Ataxia telangiectasia (A-T) patients are characterised by very high sensitivity to DSB-inducing agents such as ionizing radiation. This radiosensitivity is revealed with an enhancement of chromosomal instability as a consequence of defective DNA repair for a small fraction of breaks located in the heterochromatin, where they are less accessible. Besides, recently it has been reported that Ataxia Telangiectasia Mutated (ATM) mediated signalling modifies chromatin structure. In order to study the impact of chromatin compaction on the chromosomal instability of A-T cells, the response to trichostatin-A, an histone deacetylase inhibitor, in normal and A-T lymphoblastoid cell lines was investigated testing its effect on chromosomal aberrations, cell cycle progression, DNA damage and repair after exposure to X-rays. The results suggest that the response to both trichostatin-A pre- and continuous treatments is independent of the presence of either functional or mutated ATM protein, as the reduction of chromosomal damage was found also in the wild-type cell line. The presence of trichostatin-A before exposure to X-rays could give rise to prompt DNA repair functioning on chromatin structure already in an open conformation. Differently, trichostatin-A post-treatment causing hyperacetylation of histone tails and reducing the heterochromatic DNA content might diminish the requirement for ATM and favour DSBs repair reducing chromosomal damage only in A-T cells. This fact could suggest that trichostatin-A post-treatment is favouring the slow component of DSB repair pathway, the one impaired in absence of a functionally ATM protein. Data obtained suggest a fundamental role of chromatin compaction on chromosomal instability in A-T cells.
    Full-text · Article · Apr 2015
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    • "Notably, DNA DSBs in heterochromatin relocalize to euchromatic regions during repair (Jakob et al. 2011), and as a consequence heterochromatic regions often appear to lack radiation-induced g-H2AX foci (Cowell et al. 2007; Kim et al. 2007; Goodarzi et al. 2008; Vasireddy et al. 2010; Chiolo et al. 2011; Jakob et al. 2011; Lafon-Hughes et al. 2013). The relocalization of heterochromatin DSBs to the periphery of heterochromatic domains is accompanied by a transient ATM-dependent chromatin relaxation (Ziv et al. 2006; Geuting et al. 2013). "
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    ABSTRACT: Homologous recombination provides high-fidelity DNA repair throughout all domains of life. Live cell fluorescence microscopy offers the opportunity to image individual recombination events in real time providing insight into the in vivo biochemistry of the involved proteins and DNA molecules as well as the cellular organization of the process of homologous recombination. Herein we review the cell biological aspects of mitotic homologous recombination with a focus on Saccharomyces cerevisiae and mammalian cells, but will also draw on findings from other experimental systems. Key topics of this review include the stoichiometry and dynamics of recombination complexes in vivo, the choreography of assembly and disassembly of recombination proteins at sites of DNA damage, the mobilization of damaged DNA during homology search, and the functional compartmentalization of the nucleus with respect to capacity of homologous recombination. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Preview · Article · Mar 2015 · Cold Spring Harbor perspectives in biology
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