Altering mammalian transcription networking with ADAADi: An inhibitor of ATP-dependent chromatin remodeling

Author:

Rakesh Radhakrishnan,Chanana Upasana Bedi,Hussain Saddam,Sharma Soni,Goel Kaveri,Bisht Deepa,Patne Ketki,Swer Pynskhem Bok,Hockensmith Joel W.,Muthuswami RohiniORCID

Abstract

Active DNA-dependent ATPase A Domain inhibitor (ADAADi) is the only known inhibitor of ATP-dependent chromatin remodeling proteins that targets the ATPase domain of these proteins. The molecule is synthesized by aminoglycoside phosphotransferase enzyme in the presence of aminoglycosides. ADAADi interacts with ATP-dependent chromatin remodeling proteins through motif Ia present in the conserved helicase domain, and thus, can potentially inhibit all members of this family of proteins. We show that mammalian cells are sensitive to ADAADi but with variable responses in different cell lines. ADAADi can be generated from a wide variety of aminoglycosides; however, cells showed differential response to ADAADi generated from various aminoglycosides. Using HeLa and DU145 cells as model system we have explored the effect of ADAADi on cellular functions. We show that the transcriptional network of a cell type is altered when treated with sub-lethal concentration of ADAADi. Although ADAADi has no known effects on DNA chemical and structural integrity, expression of DNA-damage response genes was altered. The transcripts encoding for the pro-apoptotic proteins were found to be upregulated while the anti-apoptotic genes were found to be downregulated. This was accompanied by increased apoptosis leading us to hypothesize that the ADAADi treatment promotes apoptotic-type of cell death by upregulating the transcription of pro-apoptotic genes. ADAADi also inhibited migration of cells as well as their colony forming ability leading us to conclude that the compound has effective anti-tumor properties.

Funder

Council of Scientific and Industrial Research, India

CSIR

HRD fellowship-Young Scientist from the Ministry of Health and Family Welfare, India

SERB

UGC

Publisher

Public Library of Science (PLoS)

Subject

Multidisciplinary

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