SNF2 family ATPase LSH promotes phosphorylation of H2AX and efficient repair of DNA double-strand breaks in mammalian cells

Burrage, Joe; Termanis, Ausma; Geissner, Andreas; Myant, Kevin; Gordon, Katrina E.; Stancheva, Irina

doi:10.1242/jcs.111252

Cited by 52 publications

(61 citation statements)

References 56 publications

(77 reference statements)

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“…Lymphoid-specific helicase (LSH), a protein belonging to the SNF2 family of chromatinremodeling ATPases, is critical for normal development of plants and mammals by establishing correct DNA methylation levels and patterns (5)(6)(7)(8). LSH maintains genome stability in mammalian somatic cells (9,10). LSH serves as a target for DeltaNp63al-pha driving skin tumorigenesis in vivo and co-operates with the oncogenic function of E2F3 (11,12).…”

Section: Introductionmentioning

confidence: 99%

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Yan

Liu

et al. 2016

Cancer Research

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Chromatin modification is pivotal to the epithelial-mesenchymal transition (EMT), which confers potent metastatic potential to cancer cells. Here, we report a role for the chromatin remodeling factor lymphoid-specific helicase (LSH) in nasopharyngeal carcinoma (NPC), a prevalent cancer in China. LSH expression was increased in NPC, where it was controlled by the Epstein-Barr virus-encoded protein LMP1. In NPC cells in vitro and in vivo, LSH promoted cancer progression in part by regulating expression of fumarate hydratase (FH), a core component of the tricarboxylic acid cycle. LSH bound to the FH promoter, recruiting the epigenetic silencer factor G9a to repress FH transcription. Clinically, we found that the concentration of TCA intermediates in NPC patient sera was deregulated in the presence of LSH. RNAi-mediated silencing of FH mimicked LSH overexpression, establishing FH as downstream mediator of LSH effects. The TCA intermediates a-KG and citrate potentiated the malignant character of NPC cells, in part by altering IKKa-dependent EMT gene expression. In this manner, LSH furthered malignant progression of NPC by modifying cancer cell metabolism to support EMT.

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Section: Introductionmentioning

confidence: 99%

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Yan

Liu

et al. 2016

Cancer Research

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“…HELLS has been implicated in the establishment of genome-wide methylation patterns and chromatin repression (Termanis et al, 2016;Yu et al, 2014). HELLS ATPase domain is required for these functions (Burrage et al, 2012;Ren et al, 2015;Termanis et al, 2016), and ATP is necessary for nucleosome remodeling in vitro (Jenness et al, 2018). If HELLS functioned to close chromatin in meiotic cells, we might have expected to see an increase in open chromatin or H3K4me3 level in CKO mice; instead we detected a near universal closing of chromatin at hotspots upon loss of HELLS.…”

Section: Discussionmentioning

confidence: 66%

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce

Dlamini

Ananda

et al. 2019

Preprint

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Chromatin barriers prevent spurious interactions between regulatory elements and DNAbinding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hotspots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hotspots and provide access for the DNA double-strand break (DSB) machinery. Recombination hotspots are decorated by a unique combination of histone modifications, not found at other regulatory elements. HELLS is recruited to hotspots by PRDM9, and is necessary for both histone modifications and DNA accessibility at hotspots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hotspot activation where HELLS and PRDM9 function as a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs.

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“…The decreased in DNA methylation1 (ddm1) mutant, without an SNF2 chromatin-remodeling factor that is crucial for establishing a correct methylation pattern, is generally affected in the repair of UV lightinduced damage (Qüesta et al, 2013). Whether or how these effects are linked to the methylation per se is not yet clear, as the repair function of LSH1, the mammalian protein closest to DDM1, is independent from its role in methylation but rather connected to the formation of gH2A.X foci (Burrage et al, 2012). One possibility is that DDM1 and LSH could modulate the accessibility of the lesion, as discussed previously for the other chromatin-remodeling factors.…”

Section: Chromatin Modifiers Connected With Ddrmentioning

confidence: 99%

DNA Damage Repair in the Context of Plant Chromatin

Donà

Scheid

2015

Plant Physiol.

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The integrity of DNA molecules is constantly challenged. All organisms have developed mechanisms to detect and repair multiple types of DNA lesions. The basic principles of DNA damage repair (DDR) in prokaryotes and unicellular and multicellular eukaryotes are similar, but the association of DNA with nucleosomes in eukaryotic chromatin requires mechanisms that allow access of repair enzymes to the lesions. This is achieved by chromatin-remodeling factors, and their necessity for efficient DDR has recently been demonstrated for several organisms and repair pathways. Plants share many features of chromatin organization and DNA repair with fungi and animals, but they differ in other, important details, which are both interesting and relevant for our understanding of genome stability and genetic diversity. In this Update, we compare the knowledge of the role of chromatin and chromatin-modifying factors during DDR in plants with equivalent systems in yeast and humans. We emphasize plant-specific elements and discuss possible implications.A DNA molecule in a eukaryotic chromosome has a diameter of 2 nm but a length in the range of centimeters. Being 10 7 times longer than it is wide would make it highly sensitive to breakage if it were not organized in compact and dynamic chromatin, with nucleosomes as basic units followed by multiple higher order levels of organization. Within this packaging, replication and transcription constitute an endogenous mechanical strain, while exposure of cells to physical or chemical hazard creates a wide range of DNA damage induced by external factors, including photoproducts, pyrimidine dimers, interstrand crosslinking, and single and double-strand breaks (DSBs). All organisms possess mechanisms that repair DNA molecules. DNA damage repair (DDR) systems for the various types of damage are overlapping as well as complementary, and their prevalence depends on the organism, the stage of the cell cycle, the site and the amount of damage, and the availability of intact templates. A coarse categorization distinguishes nucleotide excision repair, base excision repair, nonhomologous end joining (NHEJ), and homologous recombination (HR). Many schematic models for these DDR pathways describe the action and interaction of several repair components, but they are usually misleading in one aspect: DNA strands are illustrated as straight lines, neglecting the emerging role of chromatin for the location and the fate of DNA lesions. More realistically, we should envisage DNA lesions in the chromatin context like the leakage or burst of an in-ground pipe. Recognizing the defect, localizing it, excavating the broken parts, cleaning the ends, reconnecting them, and restoring the original state are mirrored in the subsequent steps of DDR: signaling, labeling, accessing, resecting, religating, and reassembling. Chromatin is expected to especially affect the access, resection, and restoration of the original arrangement, and several factors that can dissolve higher order structures, slide, evict, or exchange ...

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SNF2 family ATPase LSH promotes phosphorylation of H2AX and efficient repair of DNA double-strand breaks in mammalian cells

Cited by 52 publications

References 56 publications

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

Chromatin Remodeling Factor LSH Drives Cancer Progression by Suppressing the Activity of Fumarate Hydratase

HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

DNA Damage Repair in the Context of Plant Chromatin

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