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FLASH GENE

Symbol

TDP1

contributors: mct/npt/pgu - updated : 27-11-2015

HGNC name	tyrosyl-DNA phosphodiesterase 1
HGNC id	18884

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_018319 17 splicing 3763 NP_060789 68 608 - 2001 11572945 encoding the same isoform NM_001008744 16 splicing 3540 NP_001008744 68 608 - 2001 11572945 differing in the 5' UTR compared to variant 1 encoding the same isoform

EXPRESSION

Type	ubiquitous

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Lymphoid/Immune lymph node       moderately   thymus       highly Reproductive male system testis     moderately

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum skeletal     Mus musculus

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	two unusual HKD signature motifs
	two PLD phosphodiesterase domains

mono polymer

monomer

HOMOLOGY

interspecies

homolog to murine Tdp1

Homologene

FAMILY	phospholipase D superfamily
	tyrosyl-DNA phosphodiesterase family

CATEGORY

enzyme , DNA associated

SUBCELLULAR LOCALIZATION	plasma membrane
	intracellular
	intracellular,cytoplasm,organelle,mitochondria
	intracellular,nucleus
text	a fraction of the TDP1 encoded by the nuclear TDP1 gene localizes to mitochondria

basic FUNCTION	involved in repairing covalent topo-isomerase 1-DNA complexes
	remove glycolate from single-stranded DNA containing a 3'- phosphoglycolate, suggesting a role in repair of
	free-radical mediated DNA double-strand breaks
	required for repair of chromosomal single-strand breaks arising independently of DNA replication from abortive top1 activity or oxidative stress
	playing a role in the repair of DNA damage mediated by topoisomerase II
	required for neural homeostasis
	critical for DNA chromosomal single-strand breaks repair in primary neural cells and required to prevent progressive cerebellar atrophy
	hydrolyzes the phosphodiester bond between a tyrosyl moiety and a DNA 3prime-end
	playing a role in repair of 3'-phosphoglycolate-terminated DNA double-strand breaks (Zhou 2009)
	its optimal function requires its phosphorylation by ATM and/or (Das 2009)
	required for efficient repair of oxidative damage in mitochondrial DNA, and is a novel mitochondrial enzyme
	role of TDP1 in protecting against oxidative DNA damage in mitochondria
	involvement of TOP1, TDP1 , and single-strand break repair (SSBR) in modulating transcription-dependent CAG repeat contractions
	TDP1 and TDP2 fulfil overlapping roles following TOP1-induced DNA damage, but not following TOP2A-induced DNA damage
	role of cytoplasmic TDP1 is the repair of mitochondrial DNA lesions arising from oxidative stress
	role of TDP1 and APTX in mitochondrial DNA repair
	not only excises trapped topoisomerases I (Top1 in the nucleus and Top1mt in mitochondria), but also repairs oxidative damage-induced 3'-phosphoglycolates and alkylation damage-induced DNA breaks
	catalyzes the repair of 3prime-DNA adducts, such as the 3prime-phosphotyrosyl linkage of DNA topoisomerase I to DNA
	a role for TDP1 during the early stages of mammalian NHEJ (non-homologous end joining)
	functional significance of PARP1 and TDP1 interaction in the process of DNA repair
	DNA repair enzyme that removes irreversible protein-linked 3' DNA complexes, 3' phosphoglycolates, alkylation damage-induced DNA breaks, and 3' deoxyribose nucleosides
	potential role of TDP1 in both canonical non-homologous end joining and alternative end joining, but not in the homologous recombination repair pathway

CELLULAR PROCESS

nucleotide, repair

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

a component

sequestered into multi-protein single-strand break repair (SSBR) complexes by direct interaction with DNA ligase III and that these complexes are catalytically inactive in SCAN1 cells

INTERACTION

DNA

RNA

small molecule

protein	DNA ligase III
	interacting with topoisomerase II
	is a substrate for modification by the small ubiquitin-like modifier SUMO
	DNA repair partners of TDP1 include PARP1, XRCC1, ligase III and PNKP from the base excision repair (BER) pathway
	active role of TDP1 in the repair of TOP2A-induced DNA damage

cell & other

REGULATION

Other	phosphorylation at S81 mediated by the protein kinases: ataxia-telangiectasia-mutated (ATM) and DNA-dependent protein kinase PRKDC (TDP1 post-translational regulation by ATM and PRKDC)
	S81 phosphorylation enhancing TDP1 interactions with XRCC1 and promotes the recruitment of TDP1 to DNA damage sites

ASSOCIATED DISORDERS

corresponding disease(s)

SCAN1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --low   sensitizes human cells to alkylation damage and the additional depletion of apurinic/apyrimidinic endonuclease I (APE1) confers hypersensitivity above that observed for TDP1 or APE1 depletion alone

Susceptibility

To Tourette syndrome (TS)

Variant & Polymorphism other	polymorphism at position rs28365054 in the TDP1 gene had a significant difference between the TS patients (AG genotype was a risk factor for TS)

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS