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FLASH GENE

Symbol

TP53BP1

contributors: mct/ - updated : 03-11-2019

HGNC name	tumor protein p53 binding protein 1
HGNC id	11999

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two BRCT domains
	tandem Tudor domains, involved in the end joining and end protection functions , that is paramount for its localization to dysfunctional telomeres, but even without the full engagement of this domain, TP53BP1 has some ability to promote NHEJ of dysfunctional telomeres
	a glycine- and arginine-rich (GAR) motif methylated by protein arginine N-methyltransferase 1

HOMOLOGY

interspecies	homolog to murine Tp53bp1
	homolog to C.elegans c09d8.1

Homologene

FAMILY

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,nucleus,nucleoplasm,nuclear bodies
text	colocalizes with TP53BP1 at sites of DNA double-strand breaks (DSBs), but only in the G1-phase of the cell cycle
	TP53BP1 nuclear bodies shield chromosomal fragile sites sequestered in these compartments against erosion

basic FUNCTION	playing a role in p53-related signal transduction pathway
	enhancing TP53-mediated transcriptional activation
	having a role in the G2/M and the intra-S phase checkpoints
	may play a separate role during mitosis; it was shown to be phosphorylated in mitotic cells and to be loaded onto kinetochores in prophase until mid-anaphase
	having a role during mitosis or in the mitotic spindle assembly checkpoint
	seems to have distinct and independent roles in response to genotoxic stress
	with others ATM signalling mediator proteins, RNF8, RNF168 and MDC1 are also required for heterochromatic DSB repair
	main facilitator of nonhomologous end joining (NHEJ) during the S phase of the cell cycle, beyond highly specialized lymphocyte rearrangements
	inhibits homologous recombination in BRCA1-deficient cells by blocking resection of DNA breaks
	TP53BP1 nuclear bodies form around DNA lesions generated by mitotic transmission of chromosomes under replication stress
	unique function for TP53BP1 in end-joining and tumor suppression
	in addition to end joining, TP53BP1 and NHEJ1 have overlapping functions in tumor suppression
	is also present at dysfunctional telomeres, is a target of ATM that accumulates at DNA double-strand breaks and favors nonhomologous end-joining (NHEJ) repair over ATM-dependent resection and homology-directed repair
	tripartite regulation of homologous recombination by RNF8, BRCA1, and TP53BP1
	RNF168 and TP53BP1 have a similar influence on homologous recombination (HR) and also indicate that these factors may function in the same pathway to inhibit HR
	RIF1 and TP53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination
	requirement in mediating NHEJ at dysfunctional telomeres and in class switch recombination are not identical
	protects telomeres lacking TERF2 from aberrant 5prime end resection
	BRCA1 and TP53BP1 play decisive roles in the choice of DNA double-strand break repair mechanisms
	role for TP53BP1 in regulating RB1 tumor suppressor activity
	PAXIP1 status correlates with breast cancer staging, in a manner similar to what has been characterized for TP53BP1
	unique role for TP53BP1 in replication fork stability

CELLULAR PROCESS

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

pathway involving gammaH2AX–MDC1–WHSC1 regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates TP53BP1 recruitment

a component

INTERACTION

DNA

RNA

small molecule

protein	central domain of wildtype TP53
	interact with MDC1 directly through the tandem BRCT domain of MDC1 and AAs 1288–1409 of TP53BP1 (interaction playing a role in the regulation of mitosis)
	interacting with RAD18 (RAD18 promotes TP53BP1-directed DSB repair by enhancing retention of TP53BP1, possibly through an interaction between RAD18 and TP53BP1 and the modification of TP53BP1)
	interacting with RNF8 and PAXIP1 (RNF8 controls DNA damage-induced nuclear foci formation of PAXIP1, which in turn regulates TP53BP1 localization to the DNA damage sites)
	interacting with TRIM28 (phosphorylation is critical for TP53BP1-mediated repair, overall phosphorylated TRIM28 levels are only modestly affected by TP53BP1 loss)
	WHSC1 is an upstream regulator of TP53BP1 (methylates H4K20 at DSBs, which facilitates the subsequent accumulation of TP53BP1)
	role for the cysteine protease Cathepsin L (CTSL) in the degradation of TP53BP1
	TP53BP1 is imported to the nucleus through the NUP153-KPNB1 interplay
	BRCA1 antagonises TP53BP1-dependent DNA repair in S phase by inhibiting its interaction with chromatin proximal to damage sites
	RNF8 regulates BRCA1-independent homologous recombination in TP53BP1-depleted cells
	colocalizes with TP53BP1, a key DNA damage response protein, and with other factors involved in DNA repair
	RIF1 is an important contributor to the control of DSB repair by TP53BP1
	RIF1 translocates to damage sites via ATM-dependent TP53BP1 phosphorylation
	TP53BP1 promotes productive class switch recombination (CSR) and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PAXIP1
	RNF168 plays a central role in the regulation of TP53BP1 functions
	TP53BP1 recruitment requires the direct recognition of a DSB-specific histone code and its influence on pathway choice is mediated by mutual antagonism with BRCA1
	mitotic kinases phosphorylate RNF8 and TP53BP1 to inhibit their recruitment to DSB-flanking chromatin
	USP28 is recruited to double-strand breaks in a manner that requires the tandem BRCT domains of the DDR protein TP53BP1
	damage site-bound TP53BP1 whose binding signal is known to be generated by RNF8 and RNF168, and unbound bulk TP53BP1 whose ensuing degradation is regulated by RNF8 and RNF168
	UBE2L3 regulates both the steady-state and replicative stress-induced ubiquitination and proteasome-dependent degradation of the tumor suppressor TP53-binding protein 1 (TP53BP1)
	mitotic phosphorylation of TP53BP1 by PLK1 and CDK1 that impairs the ability of TP53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage
	KDM1A, RNF168 and TP53BP1 interacted with each other directly
	in cells, USP51 is recruited to chromatin after DNA damage and regulates the dynamic assembly/disassembly of TP53BP1 and BRCA1 foci
	only NUP153 is needed for proper nuclear import of TP53BP1 and SENP1-dependent sumoylation of TP53BP1
	TPX2/AURKA heterodimer, nominally considered a mitotic kinase complex, is a novel binding partner of TP53BP1
	TRIM29 is required for efficient recruitment of TP53BP1 to facilitate the nonhomologous end-joining (NHEJ) pathway and thereby suppress the HR pathway in response to DNA DSBs.

cell & other

REGULATION

Other	UV light-induced phosphorylation
	BRCA1 loss activates CTSL1-mediated degradation of TP53BP1
	dephosphorylation by PPP4C enables the recruitment of TP53BP1 to double-strand DNA breaks
	acetylation limits TP53BP1 association with damaged chromatin to promote homologous recombination
	phosphorylation of TP53BP1 at the N terminus is involved in the replicative stress-induced TP53BP1 degradation

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --other   Riddle disease associated with defects in TP53BP1-mediated DNA damage signaling constitutional         exclusion of TP53BP1 has a critical role in preventing telomeres from triggering cell cycle arrest

Susceptibility

to lupus erythematosus

Variant & Polymorphism

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS