TP53BP1

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)
End	43,510,728 bp
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)
End	121,101,888 bp
RNA expression pattern
	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
	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
	7158
	27223
	ENSG00000067369
	ENSMUSG00000043909
	Q12888
	P70399
	NM_001141979; NM_001141980; NM_005657; NM_001355001
	NM_001290830; NM_013735
	NP_001135451; NP_001135452; NP_005648; NP_001341930
	NP_001277759; NP_038763
	Wikidata
View/Edit Human	View/Edit Mouse

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]

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]

TIRR (NUDT16L1)^[19]^[20]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000067369 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000043909 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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.
^ "Entrez Gene: TP53BP1 tumor protein p53 binding protein 1".
^ 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.
^ 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.
^ 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.
^ ^a ^b 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.
^ 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.
^ 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.
^ 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.
^ 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.
^ 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, 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.
^ 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.
^ Drané P, Brault ME, Cui G, Meghani K, Chaubey S, Detappe A, Parnandi N, He Y, Zheng XF, Botuyan MV, Kalousi A, Yewdell WT, Münch C, Harper JW, Chaudhuri J, Soutoglou E, Mer G, Chowdhury D (Mar 2017). "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function". Nature. 543 (7644): 211–6. doi:10.1038/nature21358. PMC 5441565. PMID 28241136.
^ Botuyan MV, Cui G, Drané P, Oliveira C, Detappe A, Brault ME, Parnandi N, Chaubey S, Thompson JR, Bragantini B, Zhao D, Chapman JR, Chowdhury D, Mer G (Jul 2018). "Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein". Nat Struct Mol Biol. 25 (7): 591–600. doi:10.1038/s41594-018-0083-z. PMC 6045459. PMID 29967536.

External links

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000067369 – Ensembl, May 2017

[refGRCm38Ensembl-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.

[pmid8016121-5] 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.

[pmid9748285-6] 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".

[pmid20453858-8] 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.

[pmid24326623-9] 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.

[pmid27217474-10] 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.

[Anglada_2020-11] 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.

[pmid17190600-12] 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.

[pmid23760478-13] 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.

[pmid12110597-14] 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.

[pmid14978302-15] 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.

[pmid11877378-16] 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.

[pmid12351827-17] 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.

[pmid15611139-18] 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.

[pmid28241136-19] Drané P, Brault ME, Cui G, Meghani K, Chaubey S, Detappe A, Parnandi N, He Y, Zheng XF, Botuyan MV, Kalousi A, Yewdell WT, Münch C, Harper JW, Chaudhuri J, Soutoglou E, Mer G, Chowdhury D (Mar 2017). "TIRR regulates 53BP1 by masking its histone methyl-lysine binding function". Nature. 543 (7644): 211–6. doi:10.1038/nature21358. PMC 5441565. PMID 28241136.

[pmid29967538-20] Botuyan MV, Cui G, Drané P, Oliveira C, Detappe A, Brault ME, Parnandi N, Chaubey S, Thompson JR, Bragantini B, Zhao D, Chapman JR, Chowdhury D, Mer G (Jul 2018). "Mechanism of 53BP1 activity regulation by RNA-binding TIRR and a designer protein". Nat Struct Mol Biol. 25 (7): 591–600. doi:10.1038/s41594-018-0083-z. PMC 6045459. PMID 29967536.

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