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Mechanisms of aberrant ribosomal RNA (rRNA) methylation and altered mRNA translation in cancers

Award Number: R01CA230746
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Mechanisms of aberrant ribosomal RNA (rRNA) methylation and altered mRNA translation in cancers - Project Summary The fidelity of mRNA translation is essential to maintain cellular homeostasis and prevent the production of aberrant proteins that could lead to disease development. Ribosomes are key components of the core translational machinery whose activity can be modulated by diverse types of nucleotide methylation on the ribosomal RNA (rRNA). A growing body of evidence indicates that the pattern of rRNA methylation is altered in cancers, leading to the synthesis of specialized ribosomes with the unique ability to translate mRNAs coding for oncogenic proteins. rRNA methylation has been shown to dynamically regulate ribosome function and influence their efficiency, accuracy and affinity for certain type of mRNAs. Hence, pathways regulating rRNA methylation can selectively drive the translation of a proteome that supports cellular transformation and tumor development. Our overarching goal is to identify pathways and key players involved in regulating the aberrant methylation of rRNA in cancers as they represent unexploited therapeutics targets. We recently uncovered that the oncogene Pelp1 is an important regulator of rRNA methylation in cancer cells. Our experimental approach, supported by preliminary data, is to elucidate the mechanisms by which Pelp1 regulates rRNA methylation and demonstrate the importance of this process for cancer progression. We hypothesize that Pelp1 supports tumorigenesis by modulating ribosomes translational activity through its ability to regulate rRNA methylation. In Aim1 we will determine whether Pelp1 regulates rRNA methylation by recruiting RNA methyltransferases to the nascent rRNA transcript. Because rRNA methylation plays an important role in regulating the translational capacity of ribosomes, we will assess whether overexpression of Pelp1 changes ribosome efficiency, fidelity, and affinity for certain types of mRNAs using translation reporter assays and a polysome profiling-sequencing approach (Aim 2). Pelp1 is overexpressed in 60-80% of breast cancers, where its level of expression directly correlates with tumor grade, metastasis, and endocrine therapy resistance. In Aim 3, we will use orthotopic mouse model of breast cancer to assess whether the ability of Pelp1 to regulate rRNA methylation is required to support tumorigenesis. Our findings suggest that by regulating rRNA methylation, Pelp1 participates in the translational reprograming of cancer cells, thereby promoting the selective translation of oncogenic genes. The successful completion of our proposed study will yield important insight into mechanisms of aberrant mRNA translation and it roles in oncogenesis.


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: 2027 ( Subtotal = -$139 )
2027	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	10/13/2026	NON-COMPETING CONTINUATION	-$139
														Subtotal = -$139

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	12/20/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $349,713 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	2/3/2023	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $349,713

Issue Date FY: 2022 ( Subtotal = $349,713 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	4/28/2022	NON-COMPETING CONTINUATION	$28,548
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	1/19/2022	NON-COMPETING CONTINUATION	$321,165
														Subtotal = $349,713

Issue Date FY: 2021 ( Subtotal = $356,850 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	2/4/2021	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $356,850

Issue Date FY: 2020 ( Subtotal = $354,563 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	2/26/2020	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2019 ( Subtotal = $352,275 )
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	2/19/2019	NEW	$352,275
2019	2019	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	3/27/2019	NEW	$0
														Subtotal = $352,275

Grand Total All Awards = $1,762,975

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Mechanisms of aberrant ribosomal RNA (rRNA) methylation and altered mRNA translation in cancers

Award Number: R01CA230746

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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