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Disruption of Cellular RNA Processing by Kaposi's Sarcoma-Associated Herpesvirus

Award Number: R01CA136367
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/12/2010
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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Disruption of Cellular RNA Processing by Kaposi's Sarcoma-Associated Herpesvirus - ABSTRACT Kaposi sarcoma-associated herpesvirus (KSHV) is the predominant etiologic agent of AIDS- associated cancers. It is endemic in many areas of Africa where, due to the extraordinarily high HIV burden, Kaposi sarcoma has emerged as one of the most common cancers. During AIDS-induced immunosuppression, KSHV replication is no longer effectively controlled, and, together with a large latently infected population of cells, contributes to disease progression and transmission. During lytic replication, KSHV dramatically remodels the host gene expression environment. A key player in this remodeling is the virally encoded, messenger RNA (mRNA) endonuclease termed SOX, which degrades cytoplasmic mRNA. SOX activity plays diverse roles in the gammaherpesvirus lifecycle and immune evasion. However, little is known about how the SOX protein is functionally regulated, either by the virus or by the host cell. Our preliminary data indicate that it is regulated both spatially and kinetically to balance the need for host shutoff against viral gene expression. In Aim I, we will define how these regulatory features impact SOX targeting of cellular and viral RNA transcripts throughout the course of KSHV lytic infection. SOX-induced cytoplasmic mRNA decay activates a feed forward loop that suppresses cellular but not viral transcription by RNA polymerase II (Pol II), effectively magnifying the depletion of the cellular mRNA pool. We previously showed that transcriptional repression requires the nuclear influx of a pool of cytoplasmic RNA binding proteins, which is triggered by mRNA. Thus, SOX profoundly alters both cellular RNA stability and synthesis and serves as a model for understanding how pathogenic stress impacts transcription. In Aim 2, we will define the sub-nuclear changes that underlie transcriptional repression during lytic KSHV infection, including how specific RNA binding proteins that are relocalized upon mRNA decay contribute mechanistically to this phenotype. Findings derived from this proposal should have a sustained impact on the field of gammaherpesvirus biology and reveal how stress or virus-induced alterations to mRNA stability influence seemingly distal components of the gene regulation circuitry.


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 = $390,632 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Biology Research	001	17	3/30/2026	NON-COMPETING CONTINUATION	$390,632
2026	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	119 CALIFORNIA HALL	BERKELEY	CA	94720	ALAMEDA	USA	Cancer Biology Research	000	15	12/23/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $390,632

Issue Date FY: 2025 ( Subtotal = $391,997 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	001	16	4/14/2025	COMPETING CONTINUATION	$391,997
2025	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	15	4/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $391,997

Issue Date FY: 2024 ( Subtotal = $366,761 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	15	5/15/2024	NON-COMPETING CONTINUATION	$366,761
														Subtotal = $366,761

Issue Date FY: 2023 ( Subtotal = $367,448 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	14	5/11/2023	NON-COMPETING CONTINUATION	$367,448
														Subtotal = $367,448

Issue Date FY: 2022 ( Subtotal = $368,103 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	13	7/21/2022	NON-COMPETING CONTINUATION	$368,103
														Subtotal = $368,103

Issue Date FY: 2021 ( Subtotal = $368,726 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	001	12	8/2/2021	NON-COMPETING CONTINUATION	$368,726
2021	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Cause and Prevention Research	000	10	3/5/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $368,726

Issue Date FY: 2020 ( Subtotal = $362,472 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Biology Research	000	11	8/31/2020	COMPETING CONTINUATION	$362,472
														Subtotal = $362,472

Issue Date FY: 2019 ( Subtotal = $335,581 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Cancer Cause and Prevention Research	000	10	8/8/2019	NON-COMPETING CONTINUATION	$335,581
														Subtotal = $335,581

Issue Date FY: 2018 ( Subtotal = $348,407 )
2018	2018	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	9	7/24/2018	NON-COMPETING CONTINUATION	$348,407
														Subtotal = $348,407

Issue Date FY: 2017 ( Subtotal = $350,631 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	8	6/21/2017	NON-COMPETING CONTINUATION	$350,631
														Subtotal = $350,631

Issue Date FY: 2016 ( Subtotal = $342,543 )
2016	2016	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	7	7/18/2016	NON-COMPETING CONTINUATION	$342,543
														Subtotal = $342,543

Issue Date FY: 2015 ( Subtotal = $359,777 )
2015	2015	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	6	9/25/2015	COMPETING CONTINUATION	$359,777
														Subtotal = $359,777

Issue Date FY: 2014 ( Subtotal = $289,524 )
2014	2014	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	5	3/24/2014	NON-COMPETING CONTINUATION	$289,524
														Subtotal = $289,524

Issue Date FY: 2013 ( Subtotal = $277,961 )
2013	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	001	4	6/28/2013	NON-COMPETING CONTINUATION	$144,894
2013	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	4	2/27/2013	NON-COMPETING CONTINUATION	$133,067
														Subtotal = $277,961

Issue Date FY: 2012 ( Subtotal = $293,015 )
2012	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	3	3/15/2012	NON-COMPETING CONTINUATION	$293,015
														Subtotal = $293,015

Issue Date FY: 2011 ( Subtotal = $290,405 )
2011	2011	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	002	2	5/20/2011	NON-COMPETING CONTINUATION	$20,957
2011	2011	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	2	2/2/2011	NON-COMPETING CONTINUATION	$269,448
2011	2010	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	001	1	2/4/2011	NEW	$0
														Subtotal = $290,405

Issue Date FY: 2010 ( Subtotal = $296,776 )
2010	2010	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Cancer Cause and Prevention Research	000	1	5/12/2010	NEW	$296,776
														Subtotal = $296,776

Grand Total All Awards = $5,800,759

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Disruption of Cellular RNA Processing by Kaposi's Sarcoma-Associated Herpesvirus

Award Number: R01CA136367

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/12/2010

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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