ATP-dependent chromatin remodeling proteins use the energy released from ATP hydrolysis to reposi... more ATP-dependent chromatin remodeling proteins use the energy released from ATP hydrolysis to reposition nucleosomes in DNA-dependent processes. These proteins are classified as SF2 helicases. SMARCAL1, a member of this protein family, is known to modulate both DNA repair and transcription by specifically recognizing DNA molecules possessing double-strand to single-strand transition regions. Mutations in this gene cause a rare autosomal recessive disorder known as Schimke Immuno-Osseous Dysplasia (SIOD). Structural studies have shown that the ATP-dependent chromatin remodeling proteins possess two RecA-like domains termed as RecA-like domain 1 and RecA-like domain 2. Using Active DNA-dependent ATPase A domain (ADAAD), the bovine homolog of SMARCAL1, as a model system we had previously shown that the RecA-like domain 1 containing helicase motifs Q, I, Ia, II, and III are sufficient for ligand binding; however, the Rec A-like domain 2 containing motifs IV, V, and VI are needed for ATP hy...
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
The G2/M checkpoint is activated on DNA damage by the ATM and ATR kinases that are regulated by p... more The G2/M checkpoint is activated on DNA damage by the ATM and ATR kinases that are regulated by post-translational modifications. In this paper, the transcriptional coregulation of ATM and ATR by SMARCAL1 and BRG1, both members of the ATPdependent chromatin remodeling protein family, is described. SMARCAL1 and BRG1 colocalize on the promoters of ATM and ATR; downregulation of SMARCAL1/BRG1 results in transcriptional repression of ATM/ATR and therefore, overriding of the G2/M checkpoint leading to mitotic abnormalities. On doxorubicin-induced DNA damage, SMARCAL1 and BRG1 are upregulated and in turn, upregulate the expression of ATM/ATR. Phosphorylation of ATM/ATR is needed for the transcriptional upregulation of SMARCAL1 and BRG1, and therefore, of ATM and ATR on DNA damage. The regulation of ATM/ATR is rendered non-functional if SMARCAL1 and/or BRG1 are absent or if the two proteins are mutated such that they are unable to hydrolyze ATP, as in for example in Schimke Immuno-Osseous Dysplasia and Coffin-Siris Syndrome. Thus, an intricate transcriptional regulation of DNA damage response genes mediated by SMARCAL1 and BRG1 is present in mammalian cells.
Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of n... more Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these ncRNA and their regulation in response to doxorubicin-induced DNA damage is not known. In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of...
The ATP-dependent chromatin remodeling factors regulate gene expression. However, it is not known... more The ATP-dependent chromatin remodeling factors regulate gene expression. However, it is not known whether these factors regulate each other. Given the ability of these factors to regulate the accessibility of DNA to transcription factors, we postulate that one ATP-dependent chromatin remodeling factor should be able to regulate the transcription of another ATP-dependent chromatin remodeling factor. In this paper, we show that BRG1 and SMARCAL1, both members of the ATP-dependent chromatin remodeling protein family, regulate each other. BRG1 binds to the SMARCAL1 promoter, while SMARCAL1 binds to the brg1 promoter. During DNA damage, the occupancy of SMARCAL1 on the brg1 promoter increases coinciding with an increase in BRG1 occupancy on the SMARCAL1 promoter, leading to increased brg1 and SMARCAL1 transcripts respectively. This is the first report of two ATP-dependent chromatin remodeling factors regulating each other.
ATP-dependent chromatin remodeling proteins use the energy released from ATP hydrolysis to reposi... more ATP-dependent chromatin remodeling proteins use the energy released from ATP hydrolysis to reposition nucleosomes in DNA-dependent processes. These proteins are classified as SF2 helicases. SMARCAL1, a member of this protein family, is known to modulate both DNA repair and transcription by specifically recognizing DNA molecules possessing double-strand to single-strand transition regions. Mutations in this gene cause a rare autosomal recessive disorder known as Schimke Immuno-Osseous Dysplasia (SIOD). Structural studies have shown that the ATP-dependent chromatin remodeling proteins possess two RecA-like domains termed as RecA-like domain 1 and RecA-like domain 2. Using Active DNA-dependent ATPase A domain (ADAAD), the bovine homolog of SMARCAL1, as a model system we had previously shown that the RecA-like domain 1 containing helicase motifs Q, I, Ia, II, and III are sufficient for ligand binding; however, the Rec A-like domain 2 containing motifs IV, V, and VI are needed for ATP hy...
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
The G2/M checkpoint is activated on DNA damage by the ATM and ATR kinases that are regulated by p... more The G2/M checkpoint is activated on DNA damage by the ATM and ATR kinases that are regulated by post-translational modifications. In this paper, the transcriptional coregulation of ATM and ATR by SMARCAL1 and BRG1, both members of the ATPdependent chromatin remodeling protein family, is described. SMARCAL1 and BRG1 colocalize on the promoters of ATM and ATR; downregulation of SMARCAL1/BRG1 results in transcriptional repression of ATM/ATR and therefore, overriding of the G2/M checkpoint leading to mitotic abnormalities. On doxorubicin-induced DNA damage, SMARCAL1 and BRG1 are upregulated and in turn, upregulate the expression of ATM/ATR. Phosphorylation of ATM/ATR is needed for the transcriptional upregulation of SMARCAL1 and BRG1, and therefore, of ATM and ATR on DNA damage. The regulation of ATM/ATR is rendered non-functional if SMARCAL1 and/or BRG1 are absent or if the two proteins are mutated such that they are unable to hydrolyze ATP, as in for example in Schimke Immuno-Osseous Dysplasia and Coffin-Siris Syndrome. Thus, an intricate transcriptional regulation of DNA damage response genes mediated by SMARCAL1 and BRG1 is present in mammalian cells.
Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of n... more Recent investigations have emphasized the role of miRNA biogenesis proteins in the synthesis of non-coding RNA when double-strand DNA breaks are induced by ionizing radiations. However, the role of these ncRNA and their regulation in response to doxorubicin-induced DNA damage is not known. In this paper, BRG1 and SMARCAL1, members of the ATP-dependent chromatin remodelling family, are shown to co-regulate the transcription of DROSHA, DGCR8, and DICER in response to double-strand DNA breaks induced by doxorubicin. Both BRG1 and SMARCAL1 are needed for the upregulation of the three miRNA biogenesis genes as absence of BRG1 results in downregulation of DGCR8 and DICER while absence of SMARCAL1 results in downregulation of DROSHA. These two proteins act in coordination to upregulate expression of DROSHA, DGCR8, and DICER when cells are treated with doxorubicin. This transcriptional regulation of the miRNA biogenesis proteins is needed for the formation of 53BP1 foci as downregulation of...
The ATP-dependent chromatin remodeling factors regulate gene expression. However, it is not known... more The ATP-dependent chromatin remodeling factors regulate gene expression. However, it is not known whether these factors regulate each other. Given the ability of these factors to regulate the accessibility of DNA to transcription factors, we postulate that one ATP-dependent chromatin remodeling factor should be able to regulate the transcription of another ATP-dependent chromatin remodeling factor. In this paper, we show that BRG1 and SMARCAL1, both members of the ATP-dependent chromatin remodeling protein family, regulate each other. BRG1 binds to the SMARCAL1 promoter, while SMARCAL1 binds to the brg1 promoter. During DNA damage, the occupancy of SMARCAL1 on the brg1 promoter increases coinciding with an increase in BRG1 occupancy on the SMARCAL1 promoter, leading to increased brg1 and SMARCAL1 transcripts respectively. This is the first report of two ATP-dependent chromatin remodeling factors regulating each other.
Uploads
Papers by Vijendra Arya