BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage

Patne, Ketki; Radhakrishnan, Ramalingam; Arya, Vijendra; Chanana, Upasana Bedi; Sethy, Ramesh; Swer, Pynskhem Bok; Muthuswami, Rohini

doi:10.1016/j.bbagrm.2017.07.003

Cited by 25 publications

(35 citation statements)

References 47 publications

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“…Further, downregulation of BRG1/SMARCAL1 results in mitotic abnormalities and an ability to override the G2/M checkpoint as these two proteins drive the transcription of ATM and ATR. As in the case of the RNAi genes (DROSHA, DGCR8 and DICER) [37], BRG1 and SMARCAL1 together co-regulate the transcription of these two kinases. Dephosphorylation of these two kinases results in shutting down of the transcriptional loop (switch OFF) ( Fig.…”

Section: Discussionmentioning

confidence: 91%

Regulation of ATM and ATR by Smarcal1 and BRG1

Sethy

Radhakrishnan

Patne

et al. 2018

Preprint

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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.

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Section: Discussionmentioning

confidence: 91%

Regulation of ATM and ATR by Smarcal1 and BRG1

Sethy

Radhakrishnan

Patne

et al. 2018

Preprint

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“…SMARCAL1 also has been reported to have a regulatory role in the transcription of a subset of genes (Baradaran-Heravi et al , 2012b, Sharma et al , 2015, Haokip et al , 2016, Patne et al , 2017). Specifically, SMARCAL1 was reported to directly modify the chromatin near promoter sequences to regulate gene expression especially in cells experiencing replication stress (Sharma et al , 2015, Haokip et al , 2016, Patne et al , 2017).…”

Section: Smarcal1mentioning

confidence: 99%

“…Specifically, SMARCAL1 was reported to directly modify the chromatin near promoter sequences to regulate gene expression especially in cells experiencing replication stress (Sharma et al , 2015, Haokip et al , 2016, Patne et al , 2017). However, SMARCAL1 binds DNA in a sequence independent manner and has not been found in complexes with any transcription factors or components of ATP-dependent chromatin remodeling complexes (Betous et al , 2012).…”

Section: Smarcal1mentioning

confidence: 99%

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

Poole

Chen

2017

Critical Reviews in Biochemistry and Molecular Biology

111

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A large number of SNF2 family, DNA and ATP-dependent motor proteins are needed during transcription, DNA replication, and DNA repair to manipulate protein-DNA interactions and change DNA structure. SMARCAL1, ZRANB3, and HLTF are three related members of this family with specialized functions that maintain genome stability during DNA replication. These proteins are recruited to replication forks through protein-protein interactions and bind DNA using both their motor and substrate recognition domains (SRD). The SRD provides specificity to DNA structures like forks and junctions and confer DNA remodeling activity to the motor domains. Remodeling reactions include fork reversal and branch migration to promote fork stabilization, template switching, and repair. Regulation ensures these powerful activities remain controlled and restricted to damaged replication forks. Inherited mutations in SMARCAL1 cause a severe developmental disorder and mutations in ZRANB3 and HLTF are linked to cancer illustrating the importance of these enzymes in ensuring complete and accurate DNA replication. In this review, we examine how these proteins function, concentrating on their common and unique attributes and regulatory mechanisms.

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“…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%

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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BRG1 and SMARCAL1 transcriptionally co-regulate DROSHA, DGCR8 and DICER in response to doxorubicin-induced DNA damage

Cited by 25 publications

References 47 publications

Regulation of ATM and ATR by Smarcal1 and BRG1

Regulation of ATM and ATR by Smarcal1 and BRG1

Functions of SMARCAL1, ZRANB3, and HLTF in maintaining genome stability

SMARCAL1, the annealing helicase and the transcriptional co‐regulator

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