TP53BP1 explained

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.^{[1] [2] [3]}

Clinical significance

53BP1 is underexpressed in most cases of triple-negative breast cancer.^[4]

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.^{[5] [6]} 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.^[7] The absence of 53BP1 at such DSBs appears to promote the alternative error-prone repair process Alt-EJ.^[7] 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^[8]
• Histone H2A or Histone H2A.X ubiquitinated at Lysine 15^[9]
• p53^{[10] [11] [12] [13]}
• DYNLL1^[14]

Further reading

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

Notes and References

1. Iwabuchi K, Bartel PL, Li B, Marraccino R, Fields S . 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 . Jun 1994 . 8016121 . 44145 . 10.1073/pnas.91.13.6098 . 1994PNAS...91.6098I . free .
2. Iwabuchi K, Li B, Massa HF, Trask BJ, Date T, Fields S . Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2 . The Journal of Biological Chemistry . 273 . 40 . 26061–8 . Oct 1998 . 9748285 . 10.1074/jbc.273.40.26061 . free .
3. Web site: Entrez Gene: TP53BP1 tumor protein p53 binding protein 1.
4. 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 . 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers . Nature Structural & Molecular Biology . 17 . 6 . 688–95 . Jun 2010 . 20453858 . 2912507 . 10.1038/nsmb.1831 .
5. Panier S, Boulton SJ . Double-strand break repair: 53BP1 comes into focus . Nat. Rev. Mol. Cell Biol. . 15 . 1 . 7–18 . 2014 . 24326623 . 10.1038/nrm3719 . 3752325 .
6. Li J, Xu X . DNA double-strand break repair: a tale of pathway choices . Acta Biochim. Biophys. Sin. (Shanghai) . 48 . 7 . 641–6 . 2016 . 27217474 . 10.1093/abbs/gmw045 . free .
7. Anglada T, Genescà A, Martín M . 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 . December 2020 . 33361520 . 7803562 . 10.18632/aging.202419 .
8. Botuyan MV, Lee J, Ward IM, Kim JE, Thompson JR, Chen J, Mer G . Structural basis for the methylation state-specific recognition of histone H4-K20 by 53BP1 and Crb2 in DNA repair . Cell . 127 . 7 . 1361–73 . Dec 2006 . 17190600 . 1804291 . 10.1016/j.cell.2006.10.043 .
9. Fradet-Turcotte A, Canny MD, Orthwein A, Leung CC, Huang H, Landry MC, Kitevski-LeBlanc J, Noordermeer SM, Sicheri F, Durocher D . 53BP1 is a reader of the DNA-damage-induced H2A Lys 15 ubiquitin mark . Nature . 499 . 7456 . 50–4 . Jun 2013 . 23760478 . 3955401 . 10.1038/nature12318 . 2013Natur.499...50F .
10. Derbyshire DJ, Basu BP, Serpell LC, Joo WS, Date T, Iwabuchi K, Doherty AJ . Crystal structure of human 53BP1 BRCT domains bound to p53 tumour suppressor . The EMBO Journal . 21 . 14 . 3863–72 . Jul 2002 . 12110597 . 126127 . 10.1093/emboj/cdf383 .
11. Ekblad CM, Friedler A, Veprintsev D, Weinberg RL, Itzhaki LS . Comparison of BRCT domains of BRCA1 and 53BP1: a biophysical analysis . Protein Science . 13 . 3 . 617–25 . Mar 2004 . 14978302 . 2286730 . 10.1110/ps.03461404 .
12. Joo WS, Jeffrey PD, Cantor SB, Finnin MS, Livingston DM, Pavletich NP . Structure of the 53BP1 BRCT region bound to p53 and its comparison to the Brca1 BRCT structure . Genes & Development . 16 . 5 . 583–93 . Mar 2002 . 11877378 . 155350 . 10.1101/gad.959202 .
13. Derbyshire DJ, Basu BP, Date T, Iwabuchi K, Doherty AJ . 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 . Oct 2002 . 12351827 . 10.1107/S0907444902010910. 2002AcCrD..58.1826D .
14. Lo KW, Kan HM, Chan LN, Xu WG, Wang KP, Wu Z, Sheng M, Zhang M . 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 . Mar 2005 . 15611139 . 10.1074/jbc.M411408200 . free .