TP53BP1

Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the TP53BP1 gene.^[5][6][7]

TP53BP1
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1GZH, 1KZY, 1XNI, 2G3R, 2IG0, 2LVM, 2MWO, 2MWP, 3LGF, 3LGL, 3LH0, 4CRI, 4RG2, 4X34, 5ECG
Identifiers
Aliases	TP53BP1, 53BP1, p202, p53BP1, TP53, TDRD30, tumor protein p53 binding protein 1
External IDs	OMIM: 605230; MGI: 1351320; HomoloGene: 4137; GeneCards: TP53BP1; OMA:TP53BP1 - orthologs
Gene location (Human) Chr. Chromosome 15 (human)[1] Band 15q15.3 Start 43,403,061 bp[1] End 43,510,728 bp[1]
Gene location (Mouse) Chr. Chromosome 2 (mouse)[2] Band 2|2 E5 Start 121,023,762 bp[2] End 121,101,888 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in pituitary gland anterior pituitary gonad ventricular zone stromal cell of endometrium Achilles tendon right uterine tube ganglionic eminence middle temporal gyrus sural nerve Top expressed in primary oocyte ascending aorta substantia nigra secondary oocyte ciliary body fossa renal corpuscle Rostral migratory stream aortic valve condyle More reference expression data BioGPS More reference expression data
Gene ontology Molecular function DNA binding transcription coregulator activity p53 binding protein binding ubiquitin modification-dependent histone binding damaged DNA binding methylated histone binding telomeric DNA binding sequence-specific DNA binding histone binding Cellular component cytoplasm nucleoplasm chromosome telomere chromosome, centromeric region kinetochore nuclear body nucleus replication fork site of double-strand break DNA repair complex Biological process regulation of transcription, DNA-templated cellular response to X-ray DNA damage checkpoint signaling positive regulation of DNA-binding transcription factor activity transcription, DNA-templated cellular response to DNA damage stimulus positive regulation of transcription, DNA-templated positive regulation of transcription by RNA polymerase II DNA repair protein homooligomerization double-strand break repair via nonhomologous end joining positive regulation of isotype switching negative regulation of double-strand break repair via homologous recombination Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 7158 27223 Ensembl ENSG00000067369 ENSMUSG00000043909 UniProt Q12888 P70399 RefSeq (mRNA) NM_001141979 NM_001141980 NM_005657 NM_001355001 NM_001290830 NM_013735 RefSeq (protein) NP_001135451 NP_001135452 NP_005648 NP_001341930 NP_001277759 NP_038763 Location (UCSC) Chr 15: 43.4 – 43.51 Mb Chr 2: 121.02 – 121.1 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Clinical significance

53BP1 is underexpressed in most cases of triple-negative breast cancer.^[8]

DNA repair

DNA double-strand breaks (DSBs) are cytotoxic damages that can be repaired either by the homologous recombinational repair (HR) pathway or by the non-homologous end-joining (NHEJ) pathway. NHEJ, although faster than HR, is less accurate. The early divergent step between the two pathways is end resection, and this step is regulated by numerous factors. In particular, BRCA1 and 53BP1 play a role in determining the balance between the two pathways.^[9][10] 53BP1 restricts resection and promotes NHEJ.

Age-associated deficient repair

Ordinarily during the G1 phase of the cell cycle, when a sister chromatid is unavailable for HR, NHEJ is the predominant pathway for repairing DNA double-strand breaks (DSBs). However, as individuals age, recruitment of 53BP1 to DSBs during G1 becomes deficient.^[11] The absence of 53BP1 at such DSBs appears to promote the alternative error-prone repair process Alt-EJ.^[11] This repair process, also referred to as microhomology-mediated end joining, is highly inaccurate and likely contributes to the aging process.

Interactions

53BP1 has been shown to physically interact with:

• Histone H4 dimethylated or monomethylated at Lysine 20^[12]
• Histone H2A or Histone H2A.X ubiquitinated at Lysine 15^[13]
• p53^{[14][15][16][17]}
• DYNLL1^[18]

References

1. GRCh38: Ensembl release 89: ENSG00000067369 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000043909 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Iwabuchi K, Bartel PL, Li B, Marraccino R, Fields S (Jun 1994). "Two cellular proteins that bind to wild-type but not mutant p53". Proceedings of the National Academy of Sciences of the United States of America. 91 (13): 6098–102. Bibcode:1994PNAS...91.6098I. doi:10.1073/pnas.91.13.6098. PMC 44145. PMID 8016121.
6. Iwabuchi K, Li B, Massa HF, Trask BJ, Date T, Fields S (Oct 1998). "Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2". The Journal of Biological Chemistry. 273 (40): 26061–8. doi:10.1074/jbc.273.40.26061. PMID 9748285.
7. "Entrez Gene: TP53BP1 tumor protein p53 binding protein 1".
8. Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q, Haffty BG, Tommiska J, Blomqvist C, Drapkin R, Adams DJ, Nevanlinna H, Bartek J, Tarsounas M, Ganesan S, Jonkers J (Jun 2010). "53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers". Nature Structural & Molecular Biology. 17 (6): 688–95. doi:10.1038/nsmb.1831. PMC 2912507. PMID 20453858.
9. Panier S, Boulton SJ (2014). "Double-strand break repair: 53BP1 comes into focus". Nat. Rev. Mol. Cell Biol. 15 (1): 7–18. doi:10.1038/nrm3719. PMID 24326623. S2CID 3752325.
10. Li J, Xu X (2016). "DNA double-strand break repair: a tale of pathway choices". Acta Biochim. Biophys. Sin. (Shanghai). 48 (7): 641–6. doi:10.1093/abbs/gmw045. PMID 27217474.
11. Anglada T, Genescà A, Martín M (December 2020). "Age-associated deficient recruitment of 53BP1 in G1 cells directs DNA double-strand break repair to BRCA1/CtIP-mediated DNA-end resection". Aging. 12 (24): 24872–24893. doi:10.18632/aging.202419. PMC 7803562. PMID 33361520.
12. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G (Dec 2006). "Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair". Cell. 127 (7): 1361–73. doi:10.1016/j.cell.2006.10.043. PMC 1804291. PMID 17190600.
13. Fradet-Turcotte A, Canny MD, Orthwein A, Leung CC, Huang H, Landry MC, Kitevski-LeBlanc J, Noordermeer SM, Sicheri F, Durocher D (Jun 2013). "53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark". Nature. 499 (7456): 50–4. Bibcode:2013Natur.499...50F. doi:10.1038/nature12318. PMC 3955401. PMID 23760478.
14. Derbyshire DJ, Basu BP, Serpell LC, Joo WS, Date T, Iwabuchi K, Doherty AJ (Jul 2002). "Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor". The EMBO Journal. 21 (14): 3863–72. doi:10.1093/emboj/cdf383. PMC 126127. PMID 12110597.
15. Ekblad CM, Friedler A, Veprintsev D, Weinberg RL, Itzhaki LS (Mar 2004). "Comparison of BRCT domains of BRCA1 and 53BP1: a biophysical analysis". Protein Science. 13 (3): 617–25. doi:10.1110/ps.03461404. PMC 2286730. PMID 14978302.
16. Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP (Mar 2002). "Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure". Genes & Development. 16 (5): 583–93. doi:10.1101/gad.959202. PMC 155350. PMID 11877378.
17. Derbyshire DJ, Basu BP, Date T, Iwabuchi K, Doherty AJ (Oct 2002). "Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor". Acta Crystallographica Section D. 58 (Pt 10 Pt 2): 1826–9. Bibcode:2002AcCrD..58.1826D. doi:10.1107/S0907444902010910. PMID 12351827.
18. Lo KW, Kan HM, Chan LN, Xu WG, Wang KP, Wu Z, Sheng M, Zhang M (Mar 2005). "The 8-kDa dynein light chain binds to p53-binding protein 1 and mediates DNA damage-induced p53 nuclear accumulation". The Journal of Biological Chemistry. 280 (9): 8172–9. doi:10.1074/jbc.M411408200. PMID 15611139.

Further reading

• Choubey D, Lengyel P (Mar 1995). "Binding of an interferon-inducible protein (p202) to the retinoblastoma protein". The Journal of Biological Chemistry. 270 (11): 6134–40. doi:10.1074/jbc.270.11.6134. PMID 7890747.
• Choubey D, Li SJ, Datta B, Gutterman JU, Lengyel P (Oct 1996). "Inhibition of E2F-mediated transcription by p202". The EMBO Journal. 15 (20): 5668–78. doi:10.1002/j.1460-2075.1996.tb00951.x. PMC 452311. PMID 8896460.
• Datta B, Li B, Choubey D, Nallur G, Lengyel P (Nov 1996). "p202, an interferon-inducible modulator of transcription, inhibits transcriptional activation by the p53 tumor suppressor protein, and a segment from the p53-binding protein 1 that binds to p202 overcomes this inhibition". The Journal of Biological Chemistry. 271 (44): 27544–55. doi:10.1074/jbc.271.44.27544. PMID 8910340.
• Wen Y, Yan DH, Spohn B, Deng J, Lin SY, Hung MC (Jan 2000). "Tumor suppression and sensitization to tumor necrosis factor alpha-induced apoptosis by an interferon-inducible protein, p202, in breast cancer cells". Cancer Research. 60 (1): 42–6. PMID 10646849.
• Xia Z, Morales JC, Dunphy WG, Carpenter PB (Jan 2001). "Negative cell cycle regulation and DNA damage-inducible phosphorylation of the BRCT protein 53BP1". The Journal of Biological Chemistry. 276 (4): 2708–18. doi:10.1074/jbc.M007665200. PMID 11042216.
• Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP (Mar 2002). "Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure". Genes & Development. 16 (5): 583–93. doi:10.1101/gad.959202. PMC 155350. PMID 11877378.
• Derbyshire DJ, Basu BP, Serpell LC, Joo WS, Date T, Iwabuchi K, Doherty AJ (Jul 2002). "Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor". The EMBO Journal. 21 (14): 3863–72. doi:10.1093/emboj/cdf383. PMC 126127. PMID 12110597.
• Lai H, Lin L, Nadji M, Lai S, Trapido E, Meng L (2002). "Mutations in the p53 tumor suppressor gene and early onset breast cancer". Cancer Biology & Therapy. 1 (1): 31–6. doi:10.4161/cbt.1.1.37. PMID 12170762.
• Derbyshire DJ, Basu BP, Date T, Iwabuchi K, Doherty AJ (Oct 2002). "Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor". Acta Crystallographica Section D. 58 (Pt 10 Pt 2): 1826–9. Bibcode:2002AcCrD..58.1826D. doi:10.1107/S0907444902010910. PMID 12351827.
• Wang B, Matsuoka S, Carpenter PB, Elledge SJ (Nov 2002). "53BP1, a mediator of the DNA damage checkpoint". Science. 298 (5597): 1435–8. Bibcode:2002Sci...298.1435W. doi:10.1126/science.1076182. PMID 12364621. S2CID 30076227.
• Richie CT, Peterson C, Lu T, Hittelman WN, Carpenter PB, Legerski RJ (Dec 2002). "hSnm1 colocalizes and physically associates with 53BP1 before and after DNA damage". Molecular and Cellular Biology. 22 (24): 8635–47. doi:10.1128/MCB.22.24.8635-8647.2002. PMC 139863. PMID 12446782.
• DiTullio RA, Mochan TA, Venere M, Bartkova J, Sehested M, Bartek J, Halazonetis TD (Dec 2002). "53BP1 functions in an ATM-dependent checkpoint pathway that is constitutively activated in human cancer". Nature Cell Biology. 4 (12): 998–1002. doi:10.1038/ncb892. PMID 12447382. S2CID 7430614.
• Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (Dec 2002). "DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1". Nature Cell Biology. 4 (12): 993–7. doi:10.1038/ncb884. PMID 12447390. S2CID 12380387.
• Peng A, Chen PL (Mar 2003). "NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage". The Journal of Biological Chemistry. 278 (11): 8873–6. doi:10.1074/jbc.C300001200. PMID 12551934.
• Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (Feb 2003). "MDC1 is a mediator of the mammalian DNA damage checkpoint". Nature. 421 (6926): 961–6. Bibcode:2003Natur.421..961S. doi:10.1038/nature01446. PMID 12607005. S2CID 4410773.
• Yan DH, Abramian A, Li Z, Ding Y, Wen Y, Liu TJ, Hunt K (Mar 2003). "P202, an interferon-inducible protein, inhibits E2F1-mediated apoptosis in prostate cancer cells". Biochemical and Biophysical Research Communications. 303 (1): 219–22. doi:10.1016/S0006-291X(03)00320-6. PMID 12646190.
• Kao GD, McKenna WG, Guenther MG, Muschel RJ, Lazar MA, Yen TJ (Mar 2003). "Histone deacetylase 4 interacts with 53BP1 to mediate the DNA damage response". The Journal of Cell Biology. 160 (7): 1017–27. doi:10.1083/jcb.200209065. PMC 2172769. PMID 12668657.
• Caldwell RB, Braselmann H, Schoetz U, Heuer S, Scherthan H, Zitzelsberger H (July 4, 2016). "Positive Cofactor 4 (PC4) is critical for DNA repair pathway re-routing in DT40 cells". Sci. Rep. 6: 28890. Bibcode:2016NatSR...628890C. doi:10.1038/srep28890. PMC 4931448. PMID 27374870.

External links

• Overview of all the structural information available in the PDB for UniProt: Q12888 (TP53-binding protein 1) at the PDBe-KB.