Lymphoid-specific helicase in epigenetics, DNA repair and cancer

Chen, Xiangyu; Li, Yamei; Rubio, Karla; Bi, Dingren; Li, Yuyi; Tang, Qinwei; Mao, Chao; Liu, Shuang; Xiao, Desheng; Barreto, Guillermo; Tao, Yongguang

doi:10.1038/s41416-021-01543-2

Cited by 17 publications

(13 citation statements)

References 91 publications

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“…In previous studies, we found that Lymphoid-specific helicase (LSH) plays a crucial part in the progression of cancer, which has major implications for the development of novel strategies to treat cancer. 10 – 16 We have confirmed that LSH can mediate p53 to regulate ferroptosis and apoptosis of tumor cells. 17 , 18 In our research, we found that LSH is a key molecule that regulates p53-related lncRNA (P53RRA).…”

Section: Introductionsupporting

confidence: 58%

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer

Long

Guo

Chen

et al. 2023

Sig Transduct Target Ther

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In the treatment of most malignancies, radiotherapy plays a significant role. However, the resistance of cancer cells to ionizing radiation (IR) is the main reason for the failure of radiotherapy, which causes tumor recurrence and metastasis. In this study, we confirmed that GPR162, an orphan receptor in the G-protein-coupled receptor family, acted as a novel radiotherapy sensitizer by interacting with the stimulator of interferon genes (STING), which targeted DNA damage responses, activated IRF3, accelerated the activation of type I interferon system, promoted the expression of chemokines including CXCL10 and CXCL4, and inhibited the occurrence and development of tumors. Interestingly, the activation of STING by overexpression of GPR162 was independent of the classical pathway of cGAS. STING inhibitors could resist the antitumor effect of overexpression of GPR162 in IR-induced mouse models. In addition, most solid tumors showed low expression of GPR162. And the higher expression of GPR162 indicated a better prognosis in patients with lung adenocarcinoma, liver cancer, breast cancer, etc. In summary, these results suggested that GPR162 may serve as a potential sensitizer of radiotherapy by promoting radiotherapy-induced STING-IFN production and increasing the expression of chemokines including CXCL10 and CXCL4 in DNA damage response, providing an alternative strategy for improving cancer radiotherapy.

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Section: Introductionsupporting

confidence: 58%

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer

Long

Guo

Chen

et al. 2023

Sig Transduct Target Ther

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“…The human and murine homologs of DDM1 are Helicase Lymphoid Specific (HELLS) and Lymphoid Specific Helicase (LSH), respectively (Chen et al, 2022). LSH is associated with heterochromatin, and LSH depletion induces DNA hypomethylation, alters chromatin accessibility, and changes histone modifications associated with repressed chromatin (Ren et al, 2015, 2019; Yu et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

The histone variant H2A.W cooperates with chromatin modifications and linker histone H1 to maintain transcriptional silencing of transposons in Arabidopsis

Bourguet

Yelagandula

et al. 2022

Preprint

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Transposable elements (TEs) are marked by a complex array of chromatin modifications, but a central unifying mechanism for how they are silenced remains elusive. Histone H3 Lysine 9 methylation (H3K9me) is an important component of heterochromatin in most eukaryotes, including plants. In flowering plants, the specialized histone variant H2A.W occupies nucleosomes found at TE sequences. This variant is deposited by the chromatin remodeler DDM1 and confers specific biophysical properties to the nucleosomes. Here we use genetic and genomic strategies to evaluate the role of H2A.W in transposon silencing in Arabidopsis. Compared with mutants lacking either H2A.W or H3K9me, the combined loss of both H2A.W and H3K9me causes a dramatic increase in both the number of expressed TEs and their expression levels. Synergistic effects are also observed when H2A.W is lost in combination with histone H1 or CH methylation, with each combination releasing silencing of specific sets of TEs. Collectively, these TEs are also upregulated in mutants lacking DDM1, which are impaired in H2A.W deposition and lose heterochromatic marks. We conclude that H2A.W acts in combination with different elements of heterochromatin to maintain silencing across a large spectrum of TEs present primarily in pericentric heterochromatin in Arabidopsis. In mammals, the DDM1 ortholog LSH deposits macroH2A to heterochromatin and silences TEs. We thus propose that specialized H2A variants localized to heterochromatin interact with a complex array of histone modifications to silence TEs in eukaryotes.

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“…HELLS may shift the relative orientation of two recA-like structural domains on itself by hydrolyzing ATP ( 43 ), hence increasing the accessibility of transcription factors to DNA ( 44 ) and carrying out the primary molecular biological function of reconstituting nucleosomes ( 45 ). As a key regulator of chromatin structure, HELLS helps maintain genome stability and repair DNA damage ( 46 ). Eukaryotic cells activate DDR after DNA damage and initiate two downstream pathways, canonical nonhomologous end joining (C-NHEJ) and homologous recombination (HR), to maintain genomic integrity.…”

Section: Discussionmentioning

confidence: 99%

Diagnostic, Prognostic, and Immunological Roles of HELLS in Pan-Cancer: A Bioinformatics Analysis

Liang

Yang

2022

Front. Immunol.

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BackgroundInappropriate repair of DNA damage drives carcinogenesis. Lymphoid-specific helicase (HELLS) is an important component of the chromatin remodeling complex that helps repair DNA through various mechanisms such as DNA methylation, histone posttranslational modification, and nucleosome remodeling. Its role in human cancer initiation and progression has garnered recent attention. Our study aims to provide a more systematic and comprehensive understanding of the role of HELLS in the development and progression of multiple malignancies through analysis of HELLS in cancers.MethodsWe explored the role of HELLS in cancers using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) database. Multiple web platforms and software were used for data analysis, including R, Cytoscape, HPA, Archs4, TISIDB, cBioPortal, STRING, GSCALite, and CancerSEA.ResultsHigh HELLS expression was found in a variety of cancers and differentially expressed across molecular and immune subtypes. HELLS was involved in many cancer pathways. Its expression positively correlated with Th2 and Tcm cells in most cancers. It also correlated with genetic markers of immunomodulators in various cancers.ConclusionsOur study elucidates the role HELLS plays in promotion, inhibition, and treatment of different cancers. HELLS is a potential cancer diagnostic and prognostic biomarker with immune, targeted, or cytotoxic therapeutic value. This work is a prerequisite to clinical validation and treatment of HELLS in cancers.

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Lymphoid-specific helicase in epigenetics, DNA repair and cancer

Cited by 17 publications

References 91 publications

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer

GPR162 activates STING dependent DNA damage pathway as a novel tumor suppressor and radiation sensitizer

The histone variant H2A.W cooperates with chromatin modifications and linker histone H1 to maintain transcriptional silencing of transposons in Arabidopsis

Diagnostic, Prognostic, and Immunological Roles of HELLS in Pan-Cancer: A Bioinformatics Analysis

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