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ATR Isomerization in Cellular Responses to UV Damage of DNA

Award Number: R01CA219342
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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ATR Isomerization in Cellular Responses to UV Damage of DNA - Summary DNA damage is a major cause of human cancers and many other human diseases. In response to DNA damage, cells activate DNA damage response (DDR) pathways such as DNA damage checkpoints, DNA repair, and apoptosis. ATR (ataxia telangiectasia and Rad3-related), a member of the phosphoinositide 3-kinase-related protein kinases (PIKK) family, is a major DNA damage checkpoint protein kinase which plays a critical role in DDR by signaling DNA damage, activating checkpoints, arresting cell cycle progression and facilitating DNA repair to restore DNA integrity. Interestingly, a body of evidence from mouse model and human epidemiologic studies shows that unlike ATM, a closely related ATR-like PIKK family member whose deficiency promotes carcinogenesis, ATR inhibition suppresses carcinogenesis. Moreover, ATR knockout is embryonically lethal. These suggest an involvement of ATR in regulating cell death. Although ATR has been extensively studied as a checkpoint kinase in DDR in the nucleus, little is known about its functions in the cytoplasm or mitochondria, the cellular organelle for activating DNA damage-induced apoptosis. A recent finding from the P.I.’s lab reveals that (a) besides its hallmark nuclear checkpoint functions, ATR is a pro-survival protein functioning directly at mitochondria against UV damage; (b) ATR contains a BH3-like domain that allows ATR to act like a Bcl-2 family protein; (c) importantly, mitochondrial ATR is a prolyl cis-isomeric form of ATR regulated by Pin1 while in contrast, nuclear ATR is a trans-isomeric form of ATR; and finally (d) mitochondria activity of ATR is independent of its checkpoint kinase activity and ATRIP. In this project, we will test the hypotheses that (1) Prolyl isomerization alters the structure of ATR, transforming ATR functions for mitochondria-specific activities to promote cell survival or nuclear functions as a DNA damage checkpoint regulator; (2) Antiapoptotic activity of ATR at mitochondria plays an important role in mediating carcinogenesis in vivo, and thus, suppressing such activity may reduce carcinogenesis/tumorigenesis and provide a strategy for cancer prevention and treatment; and (3) ATR’s trans-isomeric form is required for its DNA damage checkpoint activity, and post- translational modifications of ATR and/or ATR-ATRIP complex formation may play a role in stabilizing ATR in the trans-isomeric form in the nucleus. These hypotheses will be tested in the following specific aims. Aim 1: To define the structure-function relationships of ATR prolyl isomers, and of ATRH-tBid and ATRH- Pin1 interactions; Aim 2: To determine the role of prolyl isomerization in the nuclear functions of ATR; and Aim 3: To determine the in vivo effects of ATR isomers on carcinogenesis and tumorigenesis. The proposed studies represent an innovative effort highly relevant to cancer biology and also having implications in other human diseases such as neurodegenerative and cardiovascular diseases.


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: 2025 ( Subtotal = -$46,868 )
2025	2022	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	000	6	1/2/2025	NON-COMPETING CONTINUATION	-$46,868
														Subtotal = -$46,868

Issue Date FY: 2022 ( Subtotal = $392,700 )
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	000	6	7/12/2022	NON-COMPETING CONTINUATION	$346,350
2022	2022	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	001	6	8/17/2022	NON-COMPETING CONTINUATION	$46,350
														Subtotal = $392,700

Issue Date FY: 2021 ( Subtotal = $353,417 )
2021	2021	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	000	5	7/30/2021	NON-COMPETING CONTINUATION	$353,417
														Subtotal = $353,417

Issue Date FY: 2020 ( Subtotal = $2 )
2020	2020	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	003	4	7/21/2020	NON-COMPETING CONTINUATION	$2
2020	2019	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	000	3	11/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	002	3	2/11/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$5,296
2020	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Cause and Prevention Research	001	2	2/11/2020	NON-COMPETING CONTINUATION	-$5,296
														Subtotal = $2

Issue Date FY: 2019 ( Subtotal = $340,781 )
2019	2019	UNIVERSITY OF TOLEDO, THE	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Cause and Prevention Research	001	3	9/6/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$340,781
2019	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Cause and Prevention Research	000	2	9/6/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $340,781

Issue Date FY: 2018 ( Subtotal = $352,509 )
2018	2018	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Cause and Prevention Research	000	2	7/19/2018	NON-COMPETING CONTINUATION	$352,509
														Subtotal = $352,509

Issue Date FY: 2017 ( Subtotal = $328,513 )
2017	2017	EAST TENNESSEE STATE UNIVERSITY	1276 GILBREATH DR	JOHNSON CITY	TN	37614	WASHINGTON	USA	Cancer Cause and Prevention Research	000	1	6/12/2017	NEW	$328,513
														Subtotal = $328,513

Grand Total All Awards = $1,721,054

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ATR Isomerization in Cellular Responses to UV Damage of DNA

Award Number: R01CA219342

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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