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Elucidating the molecular mechanism and physiological relevance of TIRR mediated inhibition of p53

Award Number: R01CA264900
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Elucidating the molecular mechanism and physiological relevance of TIRR mediated inhibition of p53 - 53BP1 influences genome stability via two independent mechanisms: (i) a direct role in DNA double-strand break (DSB) repair, (ii) enhancing the activity of p53 as a transcription factor. The role of 53BP1 in DSB repair has been well described with a large body of literature. However, there is very limited understanding of how 53BP1 impacts p53 with contrasting reports on mechanism and function. Perturbing ‘normal’ mitosis caused a p53- dependent cell cycle arrest which was dependent on 53BP1 and its known interactor USP28. The suggested mechanism was that 53BP1/USP28 played a role in the stability and nuclear localization of p53. Another study reported that 53BP1/USP28 accentuated the transactivation function of p53 in response to DNA damage/stress. Loss of 53BP1/USP28 impaired the chromatin recruitment of p53 but did not impact p53 protein levels. We recently identified TIRR (Tudor Interacting Repair Regulator), as a direct interactor and regulator of 53BP1 function in DSB repair. 53BP1 recruitment to DSBs by recognition of histone H4 dimethylated at lysine K20 is inhibited by TIRR binding to the Tudor domain of 53BP1. Like p53, TIRR also binds 53BP1 independent of chromatin and DSBs. We speculated that TIRR may regulate the interaction of p53 with 53BP1, and influence 53BP1-mediated activation of p53. Loss of TIRR indeed enhanced the interaction of 53BP1 and p53 resulting in an aberrant increase in p53’s gene-transactivation function. TIRR specifically inhibited the complex formation between the Tudor domain of 53BP1 and a dimethylated form of p53 that is poised for transcriptional activation of its target genes. The impact of TIRR loss on p53 gene expression was partially rescued by depletion of 53BP1 or USP28. Therefore in Aim 1 we propose to investigate the interplay of TIRR with 53BP1/USP28 in regulating p53 transactivation function. TIRR is a RNA binding protein and our prior structural studies revealed two non- canonical RNA binding motifs in TIRR. We systematically identified TIRR bound transcripts and discovered that TIRR directly binds transcripts of several p53-regulated genes. The binding occurs near the transcription start sites (TSS) and the 3’UTR of these transcripts. Based on this data we hypothesize that TIRR may influence transcriptional elongation and mRNA stability, providing a 53BP1-independent mechanism by which TIRR regulates the p53 signaling axis. This hypothesis will be tested in Aim 2. Exploring the clinical relevance of TIRR mediated inhibition of p53, we observed that amplification of the TIRR genomic locus in human carcinomas is mutually exclusive from TP53 mutation/deletions and amplifications of the MDM2/4 loci suggesting that these are distinct mechanisms of suppressing p53 function. We generated a TIRR-deficient mouse model to investigate the idea that loss of TIRR will prevent the formation of p53-proficient tumors. Our preliminary results support this idea as these animals in the context of p53 heterozygosity, resembling Li Fraumeni syndrome (LFS) patients, have dramatically reduced tumorigenesis. In Aim 3 we will define the relevance of TIRR in cancer biology at the organismal level.


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 = $388,419 )
2025	2025	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Cause and Prevention Research	000	4	6/10/2025	NON-COMPETING CONTINUATION	$388,419
														Subtotal = $388,419

Issue Date FY: 2024 ( Subtotal = $369,493 )
2024	2024	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Cause and Prevention Research	000	3	7/3/2024	NON-COMPETING CONTINUATION	$369,493
														Subtotal = $369,493

Issue Date FY: 2023 ( Subtotal = $381,672 )
2023	2023	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	2	5/22/2023	NON-COMPETING CONTINUATION	$381,672
														Subtotal = $381,672

Issue Date FY: 2022 ( Subtotal = $389,982 )
2022	2022	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02115	SUFFOLK	USA	Cancer Cause and Prevention Research	000	1	7/1/2022	NEW	$389,982
														Subtotal = $389,982

Grand Total All Awards = $1,529,566

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Elucidating the molecular mechanism and physiological relevance of TIRR mediated inhibition of p53

Award Number: R01CA264900

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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