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The Regulatory Functions of TIRR in ...

Parnandi, Nishita.

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The Regulatory Functions of TIRR in DNA Repair and p53-Mediated Cell Fate.

Record Type:	Electronic resources : Monograph/item
Title/Author:	The Regulatory Functions of TIRR in DNA Repair and p53-Mediated Cell Fate./
Author:	Parnandi, Nishita.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2021,
Description:	115 p.
Notes:	Source: Dissertations Abstracts International, Volume: 83-02, Section: B.
Contained By:	Dissertations Abstracts International83-02B.
Subject:	Biology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=28498574
ISBN:	9798534671483

The Regulatory Functions of TIRR in DNA Repair and p53-Mediated Cell Fate.
Parnandi, Nishita.

The Regulatory Functions of TIRR in DNA Repair and p53-Mediated Cell Fate. - Ann Arbor : ProQuest Dissertations & Theses, 2021 - 115 p.

Source: Dissertations Abstracts International, Volume: 83-02, Section: B.

Thesis (Ph.D.)--Harvard University, 2021.

This item must not be sold to any third party vendors.

The tumor suppressor protein, TP53BP1, is an important DNA double-strand break (DSB) repair protein that is extensively regulated by post-translational modifications and protein-protein interactions. Our lab and others established the role of the protein, Tudor Interacting Repair Regulator (TIRR), as a regulator of 53BP1 responses in DSB repair. TIRR binds the chromatin recognition motif of 53BP1 and restricts its access to DSBs. Consequently, TIRR overexpression inhibits 53BP1 recruitment to DSBs and impairs its DNA repair function. TIRR loss, however, does not have a similar impact on 53BP1 activities in DNA repair. This raises two fundamental questions: 1) What is the cellular role of endogenous TIRR? 2) Does TIRR impact 53BP1 functions that are not reliant upon its recruitment to DSBs?Recent evidence suggests that 53BP1 is an activator of the global p53 transcriptional response. Loss of 53BP1 impairs p53-mediated cell cycle arrest and cell survival. This function of 53BP1 is completely independent of its ability to localize to damaged DNA. In this study, we elucidate how TIRR regulates 53BP1's role in the p53 transcriptional response. Here, we show that the loss of TIRR causes an aberrant increase in p53-mediated gene-transactivation. TIRR deficiency causes an abnormal induction in several key p53 pathway targets including CDKN1A (p21), MDM2, BBC3, and BAX, under different forms of cellular stress. Functionally, TIRR deficiency impacts several cell fate programs - decreased cell survival, higher senescence, and an increase in p21-mediated checkpoint arrest. From the mechanistic standpoint, TIRR modulates the stress-induced interaction of 53BP1 and p53. Our structural data demonstrates that TIRR specifically inhibits the complex formation between the Tudor domain of 53BP1 and a post-translationally modified form of p53 (dimethylated at K382) that is poised for transcriptional activation of its target genes. Analysis of cancer genomes reveals that high TIRR expression levels negatively correlate with expression of key p53 targets, thereby mimicking diminished p53 activity. Furthermore, amplifications of the TIRR genomic locus are mutually exclusive from TP53 mutation/deletions and amplifications of the MDM2/4 loci, suggesting that these are distinct mechanisms of suppressing p53 function in human cancer. Thus, we establish for the first time, the significance of TIRR as an upstream inhibitor of the 53BP1-p53 complex that regulates cell fate.

ISBN: 9798534671483Subjects--Topical Terms:

522710
Biology.
Subjects--Index Terms:

53BP1

The Regulatory Functions of TIRR in DNA Repair and p53-Mediated Cell Fate.
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520 $a The tumor suppressor protein, TP53BP1, is an important DNA double-strand break (DSB) repair protein that is extensively regulated by post-translational modifications and protein-protein interactions. Our lab and others established the role of the protein, Tudor Interacting Repair Regulator (TIRR), as a regulator of 53BP1 responses in DSB repair. TIRR binds the chromatin recognition motif of 53BP1 and restricts its access to DSBs. Consequently, TIRR overexpression inhibits 53BP1 recruitment to DSBs and impairs its DNA repair function. TIRR loss, however, does not have a similar impact on 53BP1 activities in DNA repair. This raises two fundamental questions: 1) What is the cellular role of endogenous TIRR? 2) Does TIRR impact 53BP1 functions that are not reliant upon its recruitment to DSBs?Recent evidence suggests that 53BP1 is an activator of the global p53 transcriptional response. Loss of 53BP1 impairs p53-mediated cell cycle arrest and cell survival. This function of 53BP1 is completely independent of its ability to localize to damaged DNA. In this study, we elucidate how TIRR regulates 53BP1's role in the p53 transcriptional response. Here, we show that the loss of TIRR causes an aberrant increase in p53-mediated gene-transactivation. TIRR deficiency causes an abnormal induction in several key p53 pathway targets including CDKN1A (p21), MDM2, BBC3, and BAX, under different forms of cellular stress. Functionally, TIRR deficiency impacts several cell fate programs - decreased cell survival, higher senescence, and an increase in p21-mediated checkpoint arrest. From the mechanistic standpoint, TIRR modulates the stress-induced interaction of 53BP1 and p53. Our structural data demonstrates that TIRR specifically inhibits the complex formation between the Tudor domain of 53BP1 and a post-translationally modified form of p53 (dimethylated at K382) that is poised for transcriptional activation of its target genes. Analysis of cancer genomes reveals that high TIRR expression levels negatively correlate with expression of key p53 targets, thereby mimicking diminished p53 activity. Furthermore, amplifications of the TIRR genomic locus are mutually exclusive from TP53 mutation/deletions and amplifications of the MDM2/4 loci, suggesting that these are distinct mechanisms of suppressing p53 function in human cancer. Thus, we establish for the first time, the significance of TIRR as an upstream inhibitor of the 53BP1-p53 complex that regulates cell fate.
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650 4 $a Molecular biology. $3 517296
650 4 $a Biochemistry. $3 518028
650 4 $a Genetics. $3 530508
650 4 $a DNA methylation. $3 3560639
650 4 $a Cancer. $3 634186
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650 4 $a Mutation. $3 837917
650 4 $a DNA repair. $3 916186
650 4 $a DNA damage. $3 916185
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650 4 $a Regulation. $3 3561775
650 4 $a Phosphorylation. $3 816803
650 4 $a Enzymes. $3 520899
650 4 $a Transcription factors. $3 669191
653 $a 53BP1
653 $a Cell fate
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653 $a Senescence
653 $a Tudor Interacting Repair Regulator
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