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:10.1016/j.bbagrm.2018.10.004

Cited by 20 publications

(20 citation statements)

References 73 publications

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“…The upstream DDR checkpoint kinases ATM and CHK2 have been reported to be increased in certain human pre-malignancies in vivo [ 46 ]. ATM showed a consistent upregulation in total protein ( Figure 5 b) in all PPOLs and OSCCs and has been reported following DNA damage before [ 47 ]. However, only one MPPOL line, D25, showed an increase in phosphorylation at serine 1981 (ATM-P) relative to NOKs.…”

Section: Resultssupporting

confidence: 82%

Extracellular Prostaglandins E1 and E2 and Inflammatory Cytokines Are Regulated by the Senescence Program in Potentially Premalignant Oral Keratinocytes

Karen-Ng

Ahmad

Gomes

et al. 2022

Cancers

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Potentially pre-malignant oral lesions (PPOLs) are composed of keratinocytes that are either mortal (MPPOL) or immortal (IPPOL) in vitro. We report here that MPPOL, but not generally IPPOL, keratinocytes upregulate various extracellular tumor-promoting cytokines (interleukins 6 and 8) and prostaglandins E1 (ePGE1) and E2 (ePGE2) relative to normal oral keratinocytes (NOKs). ePGE upregulation in MPPOL was independent of PGE receptor status and was associated with some but not all markers of cellular senescence. Nevertheless, ePGE upregulation was dependent on the senescence program, cyclo-oxygenase 2 (COX2) and p38 mitogen-activated protein kinase and was partially regulated by hydrocortisone. Following senescence in the absence of p16INK4A, ePGEs accumulated in parallel with a subset of tumor promoting cytokine and metalloproteinase (MMP) transcripts, all of which were ablated by ectopic telomerase. Surprisingly, ataxia telangiectasia mutated (ATM) function was not required for ePGE upregulation and was increased in expression in IPPOL keratinocytes in line with its recently reported role in telomerase function. Only ePGE1 was dependent on p53 function, suggesting that ePGEs 1 and 2 are regulated differently in oral keratinocytes. We show here that ePGE2 stimulates IPPOL keratinocyte proliferation in vitro. Therefore, we propose that MPPOL keratinocytes promote the progression of IPPOL to oral SCC in a pre-cancerous field by supplying PGEs, interleukins and MMPs in a paracrine manner. Our results suggest that the therapeutic targeting of COX-2 might be enhanced by strategies that target keratinocyte senescence.

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Section: Resultssupporting

confidence: 82%

Extracellular Prostaglandins E1 and E2 and Inflammatory Cytokines Are Regulated by the Senescence Program in Potentially Premalignant Oral Keratinocytes

Karen-Ng

Ahmad

Gomes

et al. 2022

Cancers

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“…Accumulation or persistence of R-loops could be involved in this mechanism, suggesting the need to assess whether R-loops preferentially accumulate at affected genes. Of note, both ATR- and ATM-dependent signalling have been found to be dysfunctional in cells lacking SMARCAL1, especially following induction of DSBs by doxorubicin treatment (Patne et al, 2017; Sethy et al, 2018). We, and others, have found higher activation of ATM in the absence of SMARCAL1 under unperturbed cell growth or upon perturbed replication (Couch et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…The disease is caused by bi-allelic mutations in the SMARCAL1 gene (Boerkoel et al, 2002). Although SMARCAL1 encodes for a protein homologous to the SNF2 family of chromatin remodelling factors and SMARCAL1 has been involved in transcriptional regulation (Patne et al, 2017; Sethy et al, 2018; Sharma et al, 2016), recent works proved that SMARCAL1 is critical during processing of DNA structures at replication forks to promote formation of replication intermediates through its ATP-driven strand-annealing activity (Bansbach et al, 2009; Ciccia et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes

Pugliese

Salaris

Palermo

et al. 2019

Disease Models &Amp; Mechanisms

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Schimke immuno-osseous dysplasia is an autosomal recessive genetic osteochondrodysplasia characterized by dysmorphism, spondyloepiphyseal dysplasia, nephrotic syndrome and frequently T cell immunodeficiency. Several hypotheses have been proposed to explain the pathophysiology of the disease; however, the mechanism by which SMARCAL1 mutations cause the syndrome is elusive. Here, we generated a conditional SMARCAL1 knockdown model in induced pluripotent stem cells (iPSCs) to mimic conditions associated with the severe form the disease. Using multiple cellular endpoints, we characterized this model for the presence of phenotypes linked to the replication caretaker role of SMARCAL1. Our data show that conditional knockdown of SMARCAL1 in human iPSCs induces replication-dependent and chronic accumulation of DNA damage triggering the DNA damage response. Furthermore, they indicate that accumulation of DNA damage and activation of the DNA damage response correlates with increased levels of R-loops and replication-transcription interference. Finally, we provide evidence that SMARCAL1-deficient iPSCs maintain active DNA damage response beyond differentiation, possibly contributing to the observed altered expression of a subset of germ layer-specific master genes. Confirming the relevance of SMARCAL1 loss for the observed phenotypes, they are prevented or rescued after re-expression of wild-type SMARCAL1 in our iPSC model. In conclusion, our conditional SMARCAL1 knockdown model in iPSCs may represent a powerful model when studying pathogenetic mechanisms of severe Schimke immuno-osseous dysplasia.

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“…Fun30, an ATP-dependent chromatin remodeling protein, mediates not only DNA end resection but also modulates transcriptional regulation [ 7 , 26 , 27 , 28 ]. Previously, we had shown that in mammalian cells the DNA damage response pathway is transcriptionally regulated by ATP-dependent chromatin remodeling proteins [ 29 , 30 , 31 ]. Therefore, we investigated whether Fun30 regulates genes involved in the DNA damage response pathway in C. albicans .…”

Section: Resultsmentioning

confidence: 99%

Fun30 and Rtt109 Mediate Epigenetic Regulation of the DNA Damage Response Pathway in C. albicans

Maurya

Garai

Goel

et al. 2022

JoF

Self Cite

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Fun30, an ATP-dependent chromatin remodeler from S. cerevisiae, is known to mediate both regulation of gene expression as well as DNA damage response/repair. The Fun30 from C. albicans has not yet been elucidated. We show that C. albicans Fun30 is functionally homologous to both S. cerevisiae Fun30 and human SMARCAD1. Further, C. albicans Fun30 can mediate double-strand break end resection as well as regulate gene expression. This protein regulates transcription of RTT109, TEL1, MEC1, and SNF2-genes that encode for proteins involved in DNA damage response and repair pathways. The regulation mediated by C. albicans Fun30 is dependent on its ATPase activity. The expression of FUN30, in turn, is regulated by histone H3K56 acetylation catalyzed by Rtt109 and encoded by RTT109. The RTT109Hz/FUN30Hz mutant strain shows sensitivity to oxidative stress and resistance to MMS as compared to the wild-type strain. Quantitative PCR showed that the sensitivity to oxidative stress results from downregulation of MEC1, RAD9, MRC1, and RAD5 expression; ChIP experiments showed that Fun30 but not H3K56ac regulates the expression of these genes in response to oxidative stress. In contrast, upon treatment with MMS, the expression of RAD9 is upregulated, which is modulated by both Fun30 and H3K56 acetylation. Thus, Fun30 and H3K56 acetylation mediate the response to genotoxic agents in C. albicans by regulating the expression of DNA damage response and repair pathway genes.

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Regulation of ATM and ATR by SMARCAL1 and BRG1

Cited by 20 publications

References 73 publications

Extracellular Prostaglandins E1 and E2 and Inflammatory Cytokines Are Regulated by the Senescence Program in Potentially Premalignant Oral Keratinocytes

Extracellular Prostaglandins E1 and E2 and Inflammatory Cytokines Are Regulated by the Senescence Program in Potentially Premalignant Oral Keratinocytes

Inducible SMARCAL1 knockdown in iPSC reveals a link between replication stress and altered expression of master differentiation genes

Fun30 and Rtt109 Mediate Epigenetic Regulation of the DNA Damage Response Pathway in C. albicans

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