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Mechanisms of SIRT2 Function in the DNA Damage Response

Award Number: R01CA178999
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Mechanisms of SIRT2 Function in the DNA Damage Response - PROJECT SUMMARY The objective of this proposal is to define the critical role that SIRT2 plays in directing the DNA damage response (DDR) through post-translational modification of the acetylome, which places it at the confluence of cellular metabolism, aging, carcinogenesis, and development of tumor cell resistance to anticancer agents. SIRT2 is a sirtuin family deacetylase that sense energy requirements and direct cellular processes to maintain metabolic homeostasis. Significantly, mice deficient in Sirt2 develop breast, liver, and other cancers, implying that SIRT2 is a tumor suppressor. Paradoxically, SIRT2 is overexpressed in many human cancers, including breast malignancies, and furthermore, our data suggest that high SIRT2 expression is associated with poor survival in breast cancer patients treated with adjuvant ionizing radiation (IR) and contributes to resistance to many types of cancer treatments, including IR, PARP inhibitor, and chemotherapy. However, the precise mechanisms by which SIRT2 directs the DDR to govern tumor cell treatment resistance, and moreover, how SIRT2 itself is regulated in the DDR are poorly understood. In the previous funding period, we defined a novel role for SIRT2 in directing the replication stress response (RSR) through the acetylation status of ATRIP and CDK9, and furthermore, showed that somatic SIRT2 mutations impair the activity of SIRT2 in maintaining genome integrity. In this renewal application, we propose to carry this work further by investigating a new role for SIRT2 in directing the repair of DNA double-strand breaks (DSB) through deacetylation of MRE11, identifying the upstream ubiquitination signaling events governing SIRT2 activity, and determining if SIRT2 inhibition is an effective therapeutic strategy for treatment of breast cancers resistant to conventional therapies. In this regard, we have shown that SIRT2 deacetylase activity mediates resistance of cancer cells to IR and PARP inhibitor by facilitating the end resection step in homologous recombination repair. We further identified a novel network of DDR proteins deacetylated by SIRT2 in response to IR, including MRE11. Moreover, our data suggest that SIRT2 activity but not levels is regulated in the DDR via protein monoubiquitination. We hypothesize that SIRT2 responds to upstream ubiquitination signaling to maintain genome integrity and govern breast cancer treatment resistance by directing the DDR through deacetylation of key substrates, including MRE11, which may be exploited to improve breast cancer control. We propose to: 1) Determine the role of SIRT2 in directing MRE11 in the DDR; 2) Dissect the mechanism by which SIRT2 is regulated by monoubiquitination in the DDR; 3) Establish SIRT2 as a new molecular target for breast cancer resistant to DNA damaging agents. Completion of this work will provide a detailed mechanistic understanding of how SIRT2 directs DSB repair to maintain genome integrity and govern tumor cell treatment resistance, define a novel mechanism for regulation of SIRT2 via protein monoubiquitination in the DDR, and establish proof of concept for SIRT2 inhibition as novel therapeutic approach for overcoming breast cancer treatment resistance.


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: 2026 ( Subtotal = $0 )
2026	2023	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	10	11/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $343,980 )
2023	2023	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	10	6/7/2023	NON-COMPETING CONTINUATION	$343,980
														Subtotal = $343,980

Issue Date FY: 2022 ( Subtotal = $343,980 )
2022	2022	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	9	6/27/2022	NON-COMPETING CONTINUATION	$343,980
2022	2017	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	5	8/3/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $343,980

Issue Date FY: 2021 ( Subtotal = $351,000 )
2021	2021	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	8	6/17/2021	NON-COMPETING CONTINUATION	$351,000
														Subtotal = $351,000

Issue Date FY: 2020 ( Subtotal = $351,000 )
2020	2020	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	002	7	7/1/2020	NON-COMPETING CONTINUATION	$351,000
2020	2019	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	6	1/22/2020	COMPETING CONTINUATION	$3,157
2020	2017	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	5	1/22/2020	NON-COMPETING CONTINUATION	-$3,157
														Subtotal = $351,000

Issue Date FY: 2019 ( Subtotal = $351,000 )
2019	2019	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	6	7/16/2019	COMPETING CONTINUATION	$351,000
2019	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	5	7/5/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $351,000

Issue Date FY: 2017 ( Subtotal = $323,700 )
2017	2017	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	003	5	7/20/2017	NON-COMPETING CONTINUATION	$323,700
2017	2016	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	002	4	3/9/2017	EXTENSION WITH OR WITHOUT FUNDS	$83,141
2017	2015	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	3	3/9/2017	NON-COMPETING CONTINUATION	-$8,261
2017	2015	EMORY UNIVERSITY	1599 CLIFTON RD.	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	3	3/9/2017	SUPPLEMENT FOR EXPANSION	-$74,880
														Subtotal = $323,700

Issue Date FY: 2016 ( Subtotal = $323,700 )
2016	2016	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	4	7/28/2016	EXTENSION WITH OR WITHOUT FUNDS	$323,700
														Subtotal = $323,700

Issue Date FY: 2015 ( Subtotal = $398,580 )
2015	2015	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	3	7/14/2015	NON-COMPETING CONTINUATION	$323,700
2015	2015	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	3	7/23/2015	SUPPLEMENT FOR EXPANSION	$74,880
														Subtotal = $398,580

Issue Date FY: 2014 ( Subtotal = $411,581 )
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	002	2	7/11/2014	NON-COMPETING CONTINUATION	$313,989
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	003	2	7/17/2014	SUPPLEMENT FOR EXPANSION	$72,634
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	001	1	6/4/2014	SUPPLEMENT FOR EXPANSION	-$1,212
2014	2014	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	1	5/27/2014	SUPPLEMENT FOR EXPANSION	$26,170
														Subtotal = $411,581

Issue Date FY: 2013 ( Subtotal = $323,700 )
2013	2013	EMORY UNIVERSITY	1784 N DECATUR RD,S 530 NDBLDG	ATLANTA	GA	30322	DEKALB	USA	Cancer Cause and Prevention Research	000	1	7/15/2013	NEW	$323,700
														Subtotal = $323,700

Grand Total All Awards = $3,522,221

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Mechanisms of SIRT2 Function in the DNA Damage Response

Award Number: R01CA178999

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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