Regulation of ATM and ATR by Smarcal1 and BRG1

Sethy, Ramesh; Radhakrishnan, Ramalingam; Patne, Ketki; Arya, Vijendra; Sharma, Tapan; Haokip, Dominic Thangminlen; Kumari, Reshma; Muthuswami, Rohini

doi:10.1101/261610

Cited by 8 publications

(19 citation statements)

References 62 publications

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“…were also found on the promoter of ATM gene (Fig. 2C), once again validating the experimental results obtained in previous studies 26 . Finally, we analyzed the presence of these two proteins on ABC transporters as previously BRG1 has been shown to regulate the expression of these genes in breast cancer cells 7 .…”

Section: The Transcriptomic Profile Of Hela Cells Is Altered On Treatsupporting

confidence: 92%

“…1G). The ATPase activity of these proteins is needed for co-regulating transcription [24][25][26][27] . Also, we had previously shown that cell line resistant to ADAADiN showed decreased ATPase activity of SMARCAL1 and BRG1 that manifested in alterations in the transcriptomic profile of the cells 6 .…”

Section: The Transcriptomic Profile Of Hela Cells Is Altered On Treatmentioning

confidence: 99%

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Altering Mammalian Transcription Networking with Adaadi: An Inhibitor of Atp-Dependent Chromatin Remodeling

Radhakrishnan

Hussain

Goel

et al. 2019

Preprint

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Running title: Altering mammalian transcriptome with ADAADi ABSTRACT Transcriptional control has been earnestly pursued for the regulation of cellular proliferation associated with cancer progression. The foundational paradigm of targeting transcription factors has yielded exquisite specificity, but many factors cannot yet be targeted. In contrast, targeting epigenetic factors to control chromatin structure and consequential gene expression generally yields more global effects on transcription. Our working paradigm targets neither specific transcription factors nor global epigenetic factors but ATP-dependent chromatin remodeling factors that regulate expression of a limited set of genes. Active DNA-dependent ATPase A Domain inhibitor (ADAADi) synthesized by aminoglycoside phosphotransferases is the first-inclass inhibitor of ATP-dependent chromatin remodeling proteins that targets the ATPase domain of these proteins. Mammalian cells are sensitive to ADAADi but cell lines are variable in their individual responses to the inhibitor. The ADAADi product can be generated from a variety of aminoglycoside substrates with cells showing differential responses to ADAADi depending on the starting aminoglycoside. RNA seq analysis demonstrated that targeting the chromatin remodeling by treatment with a sub-lethal concentration of ADAADi yields alterations to the transcriptional network of the cell. Predominantly, the tumor-promoting genes were repressed while pro-apoptotic and tumor suppressors genes were upregulated on treatment with ADAADi, leading to apoptotic-type cell death. Treatment with ADAADi reversed the EMT process as well as inhibited migration of cells and their colony forming ability. In conjunction with the previous report that treatment with ADAADi regresses tumors in mouse model, this chromatin remodeling inhibitor shows promising anti-tumor properties by targeting the main hallmarks of cancer.

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Section: The Transcriptomic Profile Of Hela Cells Is Altered On Treatsupporting

confidence: 92%

Section: The Transcriptomic Profile Of Hela Cells Is Altered On Treatmentioning

confidence: 99%

Altering Mammalian Transcription Networking with Adaadi: An Inhibitor of Atp-Dependent Chromatin Remodeling

Radhakrishnan

Hussain

Goel

et al. 2019

Preprint

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“…In HEK293 and MCF-7, SMARCAL1 positively regulates the expression of BRG1 but BRG1 negatively regulates the expression of SMARCAL1. 62 Biophysical studies using CD spectrophotometer has shown that the ATPase activity of ADAAD is used in remodeling the DNA into a structure that is similar to the conformation adopted by stem-loop DNA in the presence of the protein and ATP. 7,61 The ATPase activity is essential for the remodeling as both the ATPase dead mutant as well as addition of ADAADi, the specific inhibitor of ADAAD, fails to remodel the DNA.…”

Section: Smarcal1 Is a Transcriptional Co-regulatormentioning

confidence: 99%

“…These two proteins are present simultaneously on the promoters of ATM, ATR, DROSHA, DGCR8, and DICER. 62,72 On doxorubicin-induced DNA damage, SMARCAL1 and BRG1 are upregulated. 61,62,72 Furthermore, the occupancy of both SMARCAL1 and BRG1, along with RNAPII, increases at the TSS of these promoters leading to the upregulation of their expression.…”

Section: Smarcal1 and Brg1 Transcriptionally Co-regulate Dna Damagementioning

confidence: 99%

“…62,72 On doxorubicin-induced DNA damage, SMARCAL1 and BRG1 are upregulated. 61,62,72 Furthermore, the occupancy of both SMARCAL1 and BRG1, along with RNAPII, increases at the TSS of these promoters leading to the upregulation of their expression. ATM and ATR transduce the signal, while DROSHA, DGCR8, and DICER synthesize ncRNA required for 53BP1 foci formation (Figure 4b).…”

Section: Smarcal1 and Brg1 Transcriptionally Co-regulate Dna Damagementioning

confidence: 99%

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SMARCAL1, the annealing helicase and the transcriptional co‐regulator

et al. 2020

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The ATP‐dependent chromatin remodeling proteins play an important role in DNA repair. The energy released by ATP hydrolysis is used for myriad functions ranging from nucleosome repositioning and nucleosome eviction to histone variant exchange. In addition, the distant member of the family, SMARCAL1, uses the energy to reanneal stalled replication forks in response to DNA damage. Biophysical studies have shown that this protein has the unique ability to recognize and bind specifically to DNA structures possessing double‐strand to single‐strand transition regions. Mutations in SMARCAL1 have been linked to Schimke immuno‐osseous dysplasia, an autosomal recessive disorder that exhibits variable penetrance and expressivity. It has long been hypothesized that the variable expressivity and pleiotropic phenotypes observed in the patients might be due to the ability of SMARCAL1 to co‐regulate the expression of a subset of genes within the genome. Recently, the role of SMARCAL1 in regulating transcription has been delineated. In this review, we discuss the biophysical and functional properties of the protein that help it to transcriptionally co‐regulate DNA damage response as well as to bind to the stalled replication fork and stabilize it, thus ensuring genomic stability. We also discuss the role of SMARCAL1 in cancer and the possibility of using this protein as a chemotherapeutic target.

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NICD3 regulates the expression of MUC5AC and MUC2 by recruiting SMARCA4 and is involved in the differentiation of mucinous colorectal adenocarcinoma

et al. 2022

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Adenocarcinoma is the most prevalent histological subtype of colorectal cancer (CRC), with mucinous colorectal adenocarcinoma (MCA) being a unique form. Although the mucinous subtype is known to elicit a worse response to chemotherapy and immunotherapy than the nonmucinous subtype, its pathogenesis remains poorly understood. Neurogenic locus notch homolog protein 3 (NOTCH3), a member of the NOTCH subfamilies, is highly expressed in CRC. In the past three decades, many studies have been performed evaluating the biological role of NOTCH3 in CRC. However, the precise activities of NOTCH3 in MCA, as well as the mechanisms involved in its transcriptional control, are yet to be elucidated. Our finding showed that the critical transcriptional regulatory factor transcription activator BRG1 (SMARCA4) directly binds to the intracellular domain of NOTCH3 to control transcriptional regulation. Moreover, RNA‐sequencing results indicated a common targeting effect on the transcriptional activity of mucin‐5AC (MUC5AC) and mucin‐2 (MUC2) in CRC cells by NOTCH3 and SMARCA4. Furthermore, NOTCH3 was found to control the expressions of MUC5AC and MUC2 in a SMARCA4‐dependent manner. MUC5AC and MUC2, which encode two secreted mucins, are located on chromosome 11p15.5, and are linked to the development of MCA. This finding suggests that the interaction between NOTCH3 and SMARCA4 may be involved in MCA differentiation by jointly targeting MUC5AC and MUC2. Patients with MCA are often treated in accordance with CRC guidelines. Determining the relationship between NOTCH3 and SMARCA4 by demonstrating their interactions in the pathophysiology of MCA could provide novel therapeutic targets and help identify potential prognostic markers for MCA.

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Regulation of ATM and ATR by Smarcal1 and BRG1

Cited by 8 publications

References 62 publications

Altering Mammalian Transcription Networking with Adaadi: An Inhibitor of Atp-Dependent Chromatin Remodeling

Altering Mammalian Transcription Networking with Adaadi: An Inhibitor of Atp-Dependent Chromatin Remodeling

SMARCAL1, the annealing helicase and the transcriptional co‐regulator

NICD3 regulates the expression of MUC5AC and MUC2 by recruiting SMARCA4 and is involved in the differentiation of mucinous colorectal adenocarcinoma

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