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Monitoring mechanisms in mammalian ribosome biogenesis

Award Number: R01GM074091
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2005
PERIOD OF PERFORMANCE END DATE: 06/30/2015

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Monitoring mechanisms in mammalian ribosome biogenesis - DESCRIPTION (provided by applicant): Ribosomes are biological nanomachines that carry out synthesis of the entire cellular proteome. Cells require a large number of ribosomes to make proteins, especially during periods of active growth and proliferation. Each ribosome in eukaryotes is manufactured through an elaborate assembly pathway that requires more than 200 accessory protein factors. Like any other complex assembly process, biosynthesis of ribosomes generates a certain fraction of defective products and kinetically trapped intermediates. How do cells distinguish between ribosomes that are built correctly and those that are not? The main objective of the proposed research is to answer this question by elucidating the mechanisms underlying quality control of ribosome synthesis in mammalian cells. We use mouse cells in our studies because surveillance mechanisms in mammals differ in many aspects from those in other model organisms such as yeast. One of such differences is that defects in ribosome formation in mammals induce a p53-mediated nucleolar stress response, which is mechanistically not completely understood. Because the framework of preribosomes, like the ribosome itself, is made of RNA, ribonucleases play a key role in dismantling defective ribosome precursors. Here, we wish to establish the pathway through which exoribonucleases start the process of elimination of the defective preribosomes. Our project has three specific aims. 1. Determine the role of the mammalian exosome in the degradation of misassembled pre-60S subunits. We will determine whether the exosome functions in primary surveillance of misassembled pre-60S subunits or acts as a scavenger and how these activities may be regulated through candidate adaptors. 2. Identify structural features of the pre-60S subunit that control whether it will be processed or degraded. Our model is that certain components of preribosomes act as gatekeepers that control nuclease access to pre-rRNA. This will be tested by dissecting the interactions between the exonuclease Xrn2 and the 5.8S RNA-ribosomal protein complex in pre-60S subunits. 3. Determine if pre-rRNA decay products play a role in the nucleolar stress response induced by mutations in ribosome assembly factors and by anticancer drugs that block ribosome maturation, both of which significantly increase pre-rRNA breakdown by nucleases. Together, these studies will test the hypothesis that pre-rRNA surveillance by mammalian exoribonucleases serves the dual function of enabling accurate synthesis of ribosomes under normal circumstances, and initiating stress signaling when the system becomes overloaded.


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: 2017 ( Subtotal = $0 )
2017	2014	RU SCHOOL OF OSTEOPATHIC MEDICINE	42 E LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Biomedical Research and Research Training	000	10	5/4/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2016 ( Subtotal = $0 )
2016	2014	ROWAN UNIVERSITY	201 MULLICA HILL ROAD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	10	6/24/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $300,113 )
2014	2014	ROWAN UNIVERSITY	201 MULLICA HILL ROAD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	10	7/1/2014	NON-COMPETING CONTINUATION	$300,113
														Subtotal = $300,113

Issue Date FY: 2013 ( Subtotal = $289,609 )
2013	2013	ROWAN UNIVERSITY	201 MULLICA HILL ROAD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Biomedical Research and Research Training	000	9	8/1/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$289,609
														Subtotal = $289,609

Issue Date FY: 2012 ( Subtotal = $294,450 )
2012	2012	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Biomedical Research and Research Training	000	8	6/28/2012	NON-COMPETING CONTINUATION	$294,450
														Subtotal = $294,450

Issue Date FY: 2011 ( Subtotal = $294,450 )
2011	2011	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Biomedical Research and Research Training	000	7	7/4/2011	COMPETING CONTINUATION	$294,450
														Subtotal = $294,450

Issue Date FY: 2009 ( Subtotal = $230,749 )
2009	2009	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Biomedical Research and Research Training	001	6	4/3/2009	NON-COMPETING CONTINUATION	$23,075
2009	2009	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Biomedical Research and Research Training	000	6	1/16/2009	NON-COMPETING CONTINUATION	$207,674
														Subtotal = $230,749

Issue Date FY: 2008 ( Subtotal = $230,749 )
2008	2008	UMDNJ - SOUTH JERSEY CAMPUS	40 EAST LAUREL RD	STRATFORD	NJ	08084	CAMDEN	USA	Biomedical Research and Research Training	000	5	2/25/2008	NON-COMPETING CONTINUATION	$230,749
														Subtotal = $230,749

Issue Date FY: 2007 ( Subtotal = $225,959 )
2007	2007	UNIVERSITY OF ILLINOIS AT CHICAGO	809 S MARSHFIELD AVE, 511 MB	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	3	1/15/2007	NON-COMPETING CONTINUATION	$225,959
														Subtotal = $225,959

Issue Date FY: 2006 ( Subtotal = $232,708 )
2006	2006	UNIVERSITY OF ILLINOIS AT CHICAGO	809 S MARSHFIELD AVE, 511 MB	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	2	1/17/2006	NON-COMPETING CONTINUATION	$232,708
														Subtotal = $232,708

Issue Date FY: 2005 ( Subtotal = $277,308 )
2005	2005	UNIVERSITY OF ILLINOIS AT CHICAGO	809 S MARSHFIELD AVE, 511 MB	CHICAGO	IL	60612	COOK	USA	Biomedical Research and Research Training	000	1	1/14/2005	NEW	$277,308
														Subtotal = $277,308

Grand Total All Awards = $2,376,095

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Monitoring mechanisms in mammalian ribosome biogenesis

Award Number: R01GM074091

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2005

PERIOD OF PERFORMANCE END DATE: 06/30/2015

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