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Translational Control of ROS Management

Award Number: R01ES024615
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2014
PERIOD OF PERFORMANCE END DATE: 05/31/2020

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Translational Control of ROS Management - DESCRIPTION (provided by applicant): Both environmental and endogenous processes generate pathologically high levels of ROS, with subsequent damage to lipids, proteins and DNA promoting mutation and cell death. However, low levels of ROS are physiologically important in regulating cell proliferation and gene expression.1,2 Cells must thus prevent the detrimental and promote the beneficial aspects of ROS, which suggests that there are precise regulatory strategies to maintain proper ROS levels. We propose to test the hypothesis that cells manage ROS balance by turning-on and turning-off the translation of ROS detoxification and DNA damage response proteins, using the opposing activities of the RNA methyltransferases ALKBH8 and TRM9L. The underlying mechanism arises from our discovery that enzyme-catalyzed methylation signals by ALKBH8, operating at the level of tRNA modification to anticodons, can translationally up-regulate selenocysteine (Sec)-containing ROS management proteins. These RNA modifications are required for "stop-codon recoding" - the mechanism of reading internal stop-codons as Sec-codons in mRNAs for Sec-containing glutathione peroxidases (GPXs, antioxidants) and thioredoxin reductases (TrxRs, regulate ribonucleotide reductase activity to promote the DNA damage response). We hypothesize that dueling RNA modifications control stop-codon recoding to promote (ALKBH8) or prevent (TRM9L) the translation of Sec-proteins and thus regulate ROS and DNA damage responses. Further, we hypothesize that part of the process of carcinogenicity involves hijacking of RNA modification systems to turn-off stress responses and promote a pro-mutagenic program of ROS-induced DNA damage and decreased DNA repair. To facilitate our studies, we have developed a modification analysis platform to monitor 33 human tRNA modifications and we have demonstrated that anticodon modifications are significantly regulated in response to ROS stress. Together with our RNA modification analysis platform, we will use biochemical, molecular and computational analyses to test our hypothesis in a robust set of normal, cancer- derived and engineerable lines. Importantly, our studies will define a novel system of translational control of stress response, dissect the mechanism a pro-mutagenic program, and reveal new targets and strategies for cancer treatment and prevention.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = -$50 )
2021	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	000	5	11/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$50
														Subtotal = -$50

Issue Date FY: 2018 ( Subtotal = $327,935 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	001	5	8/4/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$327,935
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	002	5	8/14/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	004	5	9/22/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$112,004
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	003	4	9/22/2018	NON-COMPETING CONTINUATION	-$112,004
2018	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	000	4	8/3/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $327,935

Issue Date FY: 2017 ( Subtotal = $327,415 )
2017	2017	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	002	4	6/2/2017	NON-COMPETING CONTINUATION	$327,415
2017	2016	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	257 FULLER RD	ALBANY	NY	12203	ALBANY	USA	Environmental Health	000	3	2/9/2017	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$32,780
2017	2015	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	1400 WASHINGTON AVE	ALBANY	NY	12222	ALBANY	USA	Environmental Health	001	2	2/9/2017	SUPPLEMENT FOR EXPANSION	-$32,780
														Subtotal = $327,415

Issue Date FY: 2016 ( Subtotal = $387,345 )
2016	2016	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	3	8/4/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$387,345
														Subtotal = $387,345

Issue Date FY: 2015 ( Subtotal = $389,689 )
2015	2015	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	001	2	5/18/2015	SUPPLEMENT FOR EXPANSION	$63,654
2015	2015	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	2	5/5/2015	NON-COMPETING CONTINUATION	$326,035
														Subtotal = $389,689

Issue Date FY: 2014 ( Subtotal = $336,865 )
2014	2014	RESEARCH FOUNDATION OF STATE UNIV OF NEW YORK (SUNY)	P.O. BOX 9	ALBANY	NY	12201	ALBANY	USA	Environmental Health	000	1	8/12/2014	NEW	$336,865
														Subtotal = $336,865

Grand Total All Awards = $1,769,199

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Translational Control of ROS Management

Award Number: R01ES024615

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2014

PERIOD OF PERFORMANCE END DATE: 05/31/2020

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