Chromatin mobility and relocation in DNA repair.
TL;DR: In this article, the role that nuclear-specific filamentous actin plays in mobilizing damaged chromatin in response to DNA double-strand breaks and replication stress was examined and the authors also examined nuclear pore complexes and promyelocytic leukemia-nuclear bodies as specialized platforms for homology-directed repair.
About: This article is published in Trends in Cell Biology.The article was published on 2021-06-26 and is currently open access. It has received 18 citations till now. The article focuses on the topics: Chromatin & DNA repair.
Citations
More filters
TL;DR: The factors contributing to break repair pathway choice are addressed, the concept of biased genome evolution in filamentous pathogens is reviewed, and a model is provided that links DNA double-strand break repair pathways with properties of genome evolution.
Abstract: Abstract DNA double-strand breaks require repair or risk corrupting the language of life. To ensure genome integrity and viability, multiple DNA double-strand break repair pathways function in eukaryotes. Two such repair pathways, canonical non-homologous end joining and homologous recombination, have been extensively studied, while other pathways such as microhomology-mediated end joint and single-strand annealing, once thought to serve as back-ups, now appear to play a fundamental role in DNA repair. Here, we review the molecular details and hierarchy of these four DNA repair pathways, and where possible, a comparison for what is known between animal and fungal models. We address the factors contributing to break repair pathway choice, and aim to explore our understanding and knowledge gaps regarding mechanisms and regulation in filamentous pathogens. We additionally discuss how DNA double-strand break repair pathways influence genome engineering results, including unexpected mutation outcomes. Finally, we review the concept of biased genome evolution in filamentous pathogens, and provide a model, termed Biased Variation, that links DNA double-strand break repair pathways with properties of genome evolution. Despite our extensive knowledge for this universal process, there remain many unanswered questions, for which the answers may improve genome engineering and our understanding of genome evolution.
15 citations
TL;DR: Overall, this work presents the first photoactivator of the cGAS-STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.
Abstract: Activation of the cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way to stimulate the anticancer immune responses. Herein, two Pt(II) complexes (Pt1 and Pt2) were designed as photoactivators of the cGAS-STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activates the cGAS-STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo. Overall, we present the first photoactivator of the cGAS-STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.
10 citations
TL;DR: In this paper, the importance of chromatin context, topologically associated domains, phase separation and DNA break mobility for the establishment of repair-conducive nuclear environments is highlighted.
Abstract: Almost 25 years ago, the phosphorylation of a chromatin component, histone H2AX, was discovered as an integral part of the DNA damage response in eukaryotes. Much has been learned since then about the control of DNA repair in the context of chromatin. Recent technical and computational advances in imaging, biophysics and deep sequencing have led to unprecedented insight into nuclear organization, highlighting the impact of three-dimensional (3D) chromatin structure and nuclear topology on DNA repair. In this review, we will describe how DNA repair processes have adjusted to and in many cases adopted these organizational features to ensure accurate lesion repair. We focus on new findings that highlight the importance of chromatin context, topologically associated domains, phase separation and DNA break mobility for the establishment of repair-conducive nuclear environments. Finally, we address the consequences of aberrant 3D genome maintenance for genome instability and disease.
3 citations
TL;DR: In this paper , the effects of Rho pathway inhibition to elucidate how actin cytoskeleton disruption affects the DNA damage response and repair pathways were explored. But it remains unclear whether Rho GTPases modulate DNA damage repair and therapeutic sensitivity.
Abstract: Glioblastoma (GBM), the most common aggressive brain tumor, is characterized by rapid cellular infiltration and is routinely treated with ionizing radiation (IR), but therapeutic resistance inevitably recurs. The actin cytoskeleton of glioblastoma cells provides their high invasiveness, but it remains unclear whether Rho GTPases modulate DNA damage repair and therapeutic sensitivity. Here, we irradiated glioblastoma cells with different p53 status and explored the effects of Rho pathway inhibition to elucidate how actin cytoskeleton disruption affects the DNA damage response and repair pathways. p53-wild-type and p53-mutant cells were subjected to Rho GTPase pathway modulation by treatment with C3 toxin; knockdown of mDia-1, PFN1 and MYPT1; or treatment with F-actin polymerization inhibitors. Rho inhibition increased the sensitivity of glioma cells to IR by increasing the number of DNA double-strand breaks and delaying DNA repair by nonhomologous end-joining in p53-wild-type cells. p53 knockdown reversed this phenotype by reducing p21 expression and Rho signaling activity, whereas reactivation of p53 in p53-mutant cells by treatment with PRIMA-1 reversed these effects. The interdependence between p53 and Rho is based on nuclear p53 translocation facilitated by G-actin and enhanced by IR. Isolated IR-resistant p53-wild-type cells showed an altered morphology and increased stress fiber formation: inhibition of Rho or actin polymerization decreased cell viability in a p53-dependent manner and reversed the resistance phenotype. p53 silencing reversed the Rho inhibition-induced sensitization of IR-resistant cells. Rho inhibition also impaired the repair of IR-damaged DNA in 3D spheroid models. Rho GTPase activity and actin cytoskeleton dynamics are sensitive targets for the reversal of acquired resistance in GBM tumors with wild-type p53.
2 citations
TL;DR: In this article , the authors present an overview of the involvement of the inner nuclear membrane proteins within the hallmarks of cancer and how they may be exploited as potent anti-cancer therapeutics.
Abstract: Abstract Despite significant advances in our understanding of tumourigenesis and cancer therapeutics, cancer continues to account for 30% of worldwide deaths. Therefore, there remains an unmet need for the development of cancer therapies to improve patient quality of life and survival outcomes. The inner nuclear membrane has an essential role in cell division, cell signalling, transcription, cell cycle progression, chromosome tethering, cell migration and mitosis. Furthermore, expression of several inner nuclear membrane proteins has been shown to be frequently altered in tumour cells, resulting in the dysregulation of cellular pathways to promote tumourigenesis. However, to date, minimal research has been conducted to investigate how targeting these dysregulated and variably expressed proteins may provide a novel avenue for cancer therapies. In this review, we present an overview of the involvement of the inner nuclear membrane proteins within the hallmarks of cancer and how they may be exploited as potent anti-cancer therapeutics.
2 citations
References
More filters
TL;DR: In this paper, the kinase ATR (ATM- and Rad3-related) stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability.
Abstract: Replication stress is a complex phenomenon that has serious implications for genome stability, cell survival and human disease. Generation of aberrant replication fork structures containing single-stranded DNA activates the replication stress response, primarily mediated by the kinase ATR (ATM- and Rad3-related). Along with its downstream effectors, ATR stabilizes and helps to restart stalled replication forks, avoiding the generation of DNA damage and genome instability. Understanding this response may be key to diagnosing and treating human diseases caused by defective responses to replication stress.
1,492 citations
TL;DR: It is suggested that the presence of lengthened or stabilized telomeres is necessary for immortalization, and that this may be achieved either by the reactivation of telomerase or by a novel and as yet unidentified mechanism.
Abstract: Immortalization of human cells is often associated with reactivation of telomerase, a ribonucleoprotein enzyme that adds TTAGGG repeats onto telomeres and compensates for their shortening. We examined whether telomerase activation is necessary for immortalization. All normal human fibroblasts tested were negative for telomerase activity. Thirteen out of 13 DNA tumor virus-transformed cell cultures were also negative in the pre-crisis (i.e. non-immortalized) stage. Of 35 immortalized cell lines, 20 had telomerase activity as expected, but 15 had no detectable telomerase. The 15 telomerase-negative immortalized cell lines all had very long and heterogeneous telomeres of up to 50 kb. Hybrids between telomerase-negative and telomerase-positive cells senesced. Two senescent hybrids demonstrated telomerase activity, indicating that activation of telomerase is not sufficient for immortalization. Some hybrid clones subsequently recommenced proliferation and became immortalized either with or without telomerase activity. Those without telomerase activity also had very long and heterogeneous telomeres. Taken together, these data suggest that the presence of lengthened or stabilized telomeres is necessary for immortalization, and that this may be achieved either by the reactivation of telomerase or by a novel and as yet unidentified mechanism.
1,272 citations
TL;DR: The TTAGGG repeat arrays of mammalian telomeres pose a challenge to the DNA replication machinery, giving rise to replication-dependent defects that resemble those of aphidicolin-induced common fragile sites.
887 citations
TL;DR: It is shown that DNA sequences are copied from telomere to telomeres in an immortalized human ALT cell line, indicating that ALT occurs by means of homologous recombination and copy switching.
Abstract: Telomeres of eukaryotic chromosomes contain many tandem repeats of a G-rich sequence (for example, TTAGGG in vertebrates). In most normal human cells, telomeres shorten with each cell division, and it is proposed that this limits the number of times these cells can replicate. Telomeres may be maintained in germline cells, and in many immortalized cells and cancers, by the telomerase holoenzyme (first discovered in the ciliate Tetrahymena), which uses an RNA subunit as template for synthesis of telomeric DNA by the reverse transcriptase catalytic subunit. Some immortalized human cell lines and some tumours maintain their telomeres in the absence of any detectable telomerase activity by a mechanism referred to as alternative lengthening of telomeres (ALT). Here we show that DNA sequences are copied from telomere to telomere in an immortalized human ALT cell line, indicating that ALT occurs by means of homologous recombination and copy switching.
872 citations
TL;DR: The data suggest a conceptual framework for considering the composition and control of cellular bodies assembled through heterotypic multivalent interactions, suggesting how their compositions could be controlled by levels of PML SUMOylation or cellular mRNA concentration, respectively.
854 citations