# TP53BP1

## Overview
The TP53BP1 gene encodes the tumor protein p53 binding protein 1 (53BP1), a pivotal component in the cellular response to DNA damage. As a scaffolding protein, 53BP1 plays a critical role in the repair of DNA double-strand breaks, primarily through the non-homologous end joining (NHEJ) pathway. It is characterized by several structural domains, including BRCT repeats and tandem Tudor domains, which facilitate its recruitment to sites of DNA damage and its interaction with other proteins involved in the DNA damage response (MirzaAghazadehAttari201953BP1:; Botuyan2018Mechanism). 53BP1 also modulates p53-dependent transcriptional activities and cell-cycle checkpoints, thereby contributing to genomic stability and preventing tumorigenesis (CuellaMartin201653BP1; Lei2022Multifaceted). The gene's clinical significance is underscored by its involvement in various cancers, where alterations in TP53BP1 expression or function can influence cancer progression and patient prognosis (Yeon2017Frameshift; Gzil2020The).

## Structure
The TP53BP1 gene encodes the 53BP1 protein, a large scaffolding protein involved in DNA double-strand break repair. The protein consists of 1,972 amino acids and has a mass of over 200 kDa (MirzaAghazadehAttari201953BP1:; Lei2022Multifaceted). Structurally, 53BP1 contains several key domains, including two BRCA1 carboxy-terminal (BRCT) repeats, tandem Tudor domains, a glycine/arginine-rich region (GAR), and multiple phosphorylation sites (MirzaAghazadehAttari201953BP1:). The BRCT domains are involved in protein-protein interactions and are characterized by a central four-stranded beta-sheet with alpha-helices packed against it (Derbyshire2002Crystal). The tandem Tudor domains recognize methylated lysine residues, such as H4K20me2, which is crucial for 53BP1's recruitment to DNA damage sites (Botuyan2018Mechanism; Roy2010Structural).

Post-translational modifications, including phosphorylation by ATM kinase, play a significant role in 53BP1's function, with 32 PIK kinase and 41 cyclin-dependent kinase phosphorylation sites identified (MirzaAghazadehAttari201953BP1:). The protein's structure allows it to form oligomers and phase-separated, droplet-like foci at DNA damage sites, facilitating the concentration of repair molecules (Lei2022Multifaceted). The interaction with TIRR, which inhibits 53BP1's chromatin-binding ability, highlights the regulatory complexity of 53BP1's activity in DNA repair (Botuyan2018Mechanism).

## Function
The TP53BP1 gene encodes the 53BP1 protein, which plays a crucial role in the DNA damage response and repair processes in healthy human cells. 53BP1 is primarily involved in the non-homologous end joining (NHEJ) pathway, a key mechanism for repairing DNA double-strand breaks (DSBs). It acts as a scaffold protein, facilitating the recruitment of other proteins to DNA damage sites and promoting repair by interacting with modified histones and effector proteins through its N-terminal, minimal focus forming, and C-terminal regions (Bártová2019A; Lei2022Multifaceted).

53BP1 is also involved in regulating p53-dependent cell-cycle checkpoints and transcriptional activities. It enhances p53's binding to its responsive elements in gene promoters, such as the p21 promoter, which is essential for p53-dependent gene transactivation and maintaining G1-phase arrest following DNA damage (CuellaMartin201653BP1). The protein's BRCT domains are crucial for mediating interactions with p53, influencing p53-dependent transcription and cell cycle responses (CuellaMartin201653BP1).

In the cellular context, 53BP1 is active in the nucleus, where it forms nuclear foci at sites of DNA damage, indicating its early role in the DNA damage response (Schultz2000P53). This function is vital for maintaining genomic stability and preventing cancer development (Lei2022Multifaceted).

## Clinical Significance
Mutations and alterations in the TP53BP1 gene have significant clinical implications, particularly in cancer. In prostate cancer, decreased expression of TP53BP1 is linked to genomic instability and increased metastatic capability, especially in cases with lymph node metastases. This suggests that TP53BP1 dysfunction may contribute to cancer progression and could be used to assess the risk of metastasis and guide treatment decisions (Gzil2020The).

In colorectal cancer, TP53BP1 frameshift mutations are found in a subset of tumors with high microsatellite instability, indicating a role in tumorigenesis through inactivation (Yeon2017Frameshift). In breast cancer, TP53BP1 polymorphisms, such as Glu353Asp, are associated with more aggressive tumor characteristics, including estrogen receptor negativity and poorly differentiated tumors, although they do not significantly increase overall breast cancer risk (NAIDU2011Genetic).

In squamous cell carcinoma of the head and neck, certain TP53BP1 haplotypes are associated with a reduced risk, suggesting a protective role against this cancer type (Chen2007Polymorphic). These findings highlight the importance of TP53BP1 in cancer susceptibility and progression.

## Interactions
TP53BP1, also known as 53BP1, is involved in various interactions that are crucial for its role in DNA damage response and repair. It interacts with the tumor suppressor protein p53, enhancing p53-dependent transcriptional responses. This interaction is mediated by the BRCT domain of 53BP1, which is essential for p53 regulation but not for 53BP1's role in non-homologous end joining (NHEJ) during class switch recombination (CuellaMartin201653BP1).

53BP1 is recruited to DNA double-strand breaks (DSBs) by recognizing specific histone modifications, such as H2AK15ub and H4K20me2. The protein TIRR inhibits 53BP1's ability to bind to these modifications, acting as an 'off switch' by blocking the methylated chromatin-binding surface of 53BP1. This inhibition can be relieved by RNA molecules, which facilitate 53BP1 recruitment to DSBs (Botuyan2018Mechanism).

53BP1 also interacts with USP28, a deubiquitinating enzyme, to co-regulate p53-dependent cell-cycle checkpoints and transcriptional activities. This interaction enhances p53 DNA-binding activity and is crucial for maintaining cell-cycle arrest following stress signals (CuellaMartin201653BP1).

Additionally, 53BP1 forms complexes with proteins like Rif1 and PTIP to inhibit nucleolytic processing of DNA ends, promoting NHEJ over homologous recombination (CuellaMartin201653BP1).


## References


[1. (CuellaMartin201653BP1) Raquel Cuella-Martin, Catarina Oliveira, Helen E. Lockstone, Suzanne Snellenberg, Natalia Grolmusova, and J. Ross Chapman. 53bp1 integrates dna repair and p53-dependent cell fate decisions via distinct mechanisms. Molecular Cell, 64(1):51–64, October 2016. URL: http://dx.doi.org/10.1016/j.molcel.2016.08.002, doi:10.1016/j.molcel.2016.08.002. This article has 148 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1016/j.molcel.2016.08.002)

[2. (Derbyshire2002Crystal) D. J. Derbyshire. Crystal structure of human 53bp1 brct domains bound to p53 tumour suppressor. The EMBO Journal, 21(14):3863–3872, July 2002. URL: http://dx.doi.org/10.1093/emboj/cdf383, doi:10.1093/emboj/cdf383. This article has 151 citations.](https://doi.org/10.1093/emboj/cdf383)

[3. (Chen2007Polymorphic) Kexin Chen, Zhibin Hu, Li-E Wang, Wei Zhang, Adel K. El-Naggar, Erich M. Sturgis, and Qingyi Wei. Polymorphic tp53bp1 and tp53 gene interactions associated with risk of squamous cell carcinoma of the head and neck. Clinical Cancer Research, 13(14):4300–4305, July 2007. URL: http://dx.doi.org/10.1158/1078-0432.ccr-07-0469, doi:10.1158/1078-0432.ccr-07-0469. This article has 21 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1158/1078-0432.ccr-07-0469)

[4. (Schultz2000P53) Linda B. Schultz, Nabil H. Chehab, Asra Malikzay, and Thanos D. Halazonetis. P53 binding protein 1 (53bp1) is an early participant in the cellular response to dna double-strand breaks. The Journal of Cell Biology, 151(7):1381–1390, December 2000. URL: http://dx.doi.org/10.1083/jcb.151.7.1381, doi:10.1083/jcb.151.7.1381. This article has 724 citations.](https://doi.org/10.1083/jcb.151.7.1381)

[5. (NAIDU2011Genetic) RAKESH NAIDU, YIP CHENG HAR, and NUR AISHAH MOHD TAIB. Genetic polymorphisms of tp53-binding protein 1 (tp53bp1) gene and association with breast cancer risk: tp53bp1 polymorphisms in breast cancer. APMIS, 119(7):460–467, April 2011. URL: http://dx.doi.org/10.1111/j.1600-0463.2011.02753.x, doi:10.1111/j.1600-0463.2011.02753.x. This article has 4 citations and is from a peer-reviewed journal.](https://doi.org/10.1111/j.1600-0463.2011.02753.x)

[6. (Gzil2020The) Arkadiusz Gzil, Damian Jaworski, Paulina Antosik, Izabela Zarębska, Justyna Durślewicz, Joanna Dominiak, Anna Kasperska, Izabela Neska-Długosz, Dariusz Grzanka, and Łukasz Szylberg. The impact of tp53bp1 and mlh1 on metastatic capability in cases of locally advanced prostate cancer and their usefulness in clinical practice. Urologic Oncology: Seminars and Original Investigations, 38(6):600.e17-600.e26, June 2020. URL: http://dx.doi.org/10.1016/j.urolonc.2020.02.012, doi:10.1016/j.urolonc.2020.02.012. This article has 1 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.urolonc.2020.02.012)

[7. (MirzaAghazadehAttari201953BP1:) Mohammad Mirza-Aghazadeh-Attari, Amir Mohammadzadeh, Bahman Yousefi, Ainaz Mihanfar, Ansar Karimian, and Maryam Majidinia. 53bp1: a key player of dna damage response with critical functions in cancer. DNA Repair, 73:110–119, January 2019. URL: http://dx.doi.org/10.1016/j.dnarep.2018.11.008, doi:10.1016/j.dnarep.2018.11.008. This article has 88 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.dnarep.2018.11.008)

[8. (Botuyan2018Mechanism) Maria Victoria Botuyan, Gaofeng Cui, Pascal Drané, Catarina Oliveira, Alexandre Detappe, Marie Eve Brault, Nishita Parnandi, Shweta Chaubey, James R. Thompson, Benoît Bragantini, Debiao Zhao, J. Ross Chapman, Dipanjan Chowdhury, and Georges Mer. Mechanism of 53bp1 activity regulation by rna-binding tirr and a designer protein. Nature Structural & Molecular Biology, 25(7):591–600, July 2018. URL: http://dx.doi.org/10.1038/s41594-018-0083-z, doi:10.1038/s41594-018-0083-z. This article has 34 citations.](https://doi.org/10.1038/s41594-018-0083-z)

[9. (Lei2022Multifaceted) Tiantian Lei, Suya Du, Zhe Peng, and Lin Chen. Multifaceted regulation and functions of 53bp1 in nhej‑mediated dsb repair (review). International Journal of Molecular Medicine, May 2022. URL: http://dx.doi.org/10.3892/ijmm.2022.5145, doi:10.3892/ijmm.2022.5145. This article has 19 citations and is from a peer-reviewed journal.](https://doi.org/10.3892/ijmm.2022.5145)

[10. (Bártová2019A) Eva Bártová, Soňa Legartová, Miroslav Dundr, and Jana Suchánková. A role of the 53bp1 protein in genome protection: structural and functional characteristics of 53bp1-dependent dna repair. Aging, 11(8):2488–2511, April 2019. URL: http://dx.doi.org/10.18632/aging.101917, doi:10.18632/aging.101917. This article has 15 citations and is from a peer-reviewed journal.](https://doi.org/10.18632/aging.101917)

[11. (Yeon2017Frameshift) Su Yeon Yeon, Yun Sol Jo, Eun Ji Choi, Min Sung Kim, Nam Jin Yoo, and Sug Hyung Lee. Frameshift mutations in repeat sequences of ank3, hacd4, tcp10l, tp53bp1, mfn1, lcmt2, rnmt, trmt6, mettl8 and mettl16 genes in colon cancers. Pathology & Oncology Research, 24(3):617–622, August 2017. URL: http://dx.doi.org/10.1007/s12253-017-0287-2, doi:10.1007/s12253-017-0287-2. This article has 42 citations.](https://doi.org/10.1007/s12253-017-0287-2)

[12. (Roy2010Structural) Siddhartha Roy, Catherine A. Musselman, Ioulia Kachirskaia, Ryo Hayashi, Karen C. Glass, Jay C. Nix, Or Gozani, Ettore Appella, and Tatiana G. Kutateladze. Structural insight into p53 recognition by the 53bp1 tandem tudor domain. Journal of Molecular Biology, 398(4):489–496, May 2010. URL: http://dx.doi.org/10.1016/j.jmb.2010.03.024, doi:10.1016/j.jmb.2010.03.024. This article has 46 citations and is from a domain leading peer-reviewed journal.](https://doi.org/10.1016/j.jmb.2010.03.024)