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Elucidating the Quality Control Pathways that Cope with Mutant Ribosomal RNA in Mammalian Cells

Award Number: F32GM143875
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Elucidating the Quality Control Pathways that Cope with Mutant Ribosomal RNA in Mammalian Cells - PROJECT SUMMARY Protein production is absolutely essential and faulty translation has been linked to a wide-range of diseases including cancer, neurodegeneration and a class of predominantly developmental disorders known as ribosomopathies. In order to ensure faithful translation of the genetic code, cells need to monitor the integrity of all components of the translation apparatus, including mRNAs, tRNAs, and ribosomes. Although the quality control mechanisms that monitor mRNAs and tRNAs are relatively well characterized, very little is known about quality control of the ribosome itself. The eukaryotic ribosome is a complex molecular machine consisting of 4 ribosomal RNAs (rRNA) and 80 proteins, and all these components are subjected to mutations, oxidative stress, and UV radiation. Notably, the rRNA carries out the core enzymatic functions of the ribosome during translation. Despite the importance of rRNA to ribosomal function and human health, the quality control mechanisms that cope with the presence of defective rRNA have not been studied in mammalian cells. Previous work in yeast has discovered that rRNAs harboring mutations are preferentially degraded, confirming the existence of quality control mechanisms targeting faulty rRNA. However, the components involved in the detection and degradation of these rRNAs remain poorly characterized. This knowledge gap is primarily due to technological constraints, including limited rRNA detection methods and appropriate reporter systems geared for genome-wide screens. Recent technological advances have primed the field for unbiased and mechanistic studies. Due to the critical nature of ribosomal quality control to human health, I seek to define the quality control mechanisms that mammalian cells impart on rRNA. I have engineered a mammalian fluorescent rRNA reporter that can be paired with both unbiased genetic screening and hypothesis-driven approaches. Taking advantage of this unique tool, I will determine how human cells cope with defective ribosomes harboring mutant 18S rRNA, the rRNA component of the small ribosomal subunit. I will first characterize how mutations in the 18S rRNAs interfere with translation. Second, I will determine the fate of defective 18S rRNA in mammalian cells. Lastly, I will identify the mammalian factors coping with defective rRNA. Together, the proposed studies will for the first time delineate mammalian rRNA quality control mechanisms, and provide the foundation for understanding how dysregulation of this process leads to human disease.


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 = $0 )
2025	2023	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	5/27/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $69,500 )
2023	2023	CARNEGIE INSTITUTION OF WASHINGTON	5241 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	2	7/25/2023	NON-COMPETING CONTINUATION	$69,500
														Subtotal = $69,500

Issue Date FY: 2022 ( Subtotal = $67,174 )
2022	2022	CARNEGIE INSTITUTION OF WASHINGTON	5251 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	000	1	4/8/2022	NEW	$65,994
2022	2022	CARNEGIE INSTITUTION OF WASHINGTON	5251 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	002	1	7/29/2022	NEW	$1,180
2022	2022	CARNEGIE INSTITUTION OF WASHINGTON	5251 BROAD BRANCH RD NW	WASHINGTON	DC	20015	DISTRICT OF COLUMBIA	USA	Biomedical Research and Research Training	001	1	4/8/2022	NEW	$0
														Subtotal = $67,174

Grand Total All Awards = $136,674

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Elucidating the Quality Control Pathways that Cope with Mutant Ribosomal RNA in Mammalian Cells

Award Number: F32GM143875

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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