Table 1.

Pathogenicity of topoisomerase malfunctions and phenotypic dysfunctions

Gene	Clinical manifestations	Vertebrate cell line models	Mouse knockout phenotypes	Fruitfly knockout phenotype	Yeast knockout phenotypes
TOP1	TOP1 antibody (SCL70) autoimmune syndromes Aicardi–Goutières syndrome147 Autism62	Reduced TOP1 expression causes replication stalling, R-loops and genome instability67,165	Essential for early embryogenesis166 Genomic instability and early neurodegeneration in the brain65	TOP1 is essential for multiple cellular functions319,320	Top1 knockout causes slow growth and accelerated ageing phenotype (ribosomal DNA circles)321
TOP1MT	Unknown. SNPs are frequent322	TOP1MT overexpression reduces mtDNA transcription323,324 Expression of TOP1MT (mouse T546-N550H; human T554A-N558H) producing irreversible TOP1MTccs induces mtDNA degradation202	Dispensable174,176,325,326 Reduced tissue regeneration174 Carcinogenesis176 Reduced spermatogenesis327 Reduced mtDNA replication174 Reduced mitochondrial transcription175,324 Reduced mitochondrial translation176
TOP2A	Amplified in HER2-positive breast cancers (chromosome 17q amplicon) TOP2 antibodies found in the autoimmunity syndrome lupus328 and in cancer329	Selectively expressed and essential in proliferating cells33,330 Non-essential in quiescent cell lines	–	–	Top2 is essential for termination of DNA replication and chromosome segregation at mitosis115,321
TOP2B	Mutations associated with B cell deficiency, global developmental delay and autism spectrum disorder331–333	Non-essential in cell lines34,334	Perinatal lethality owing to defects in neuronal differentiation and connectivity182,183,335 Conditional knockout: role in corticogenesis182, and retinal173 and ovarian development336 Depletion by local injection: defective consolidation of fear memory337
TOP3A	Bloom syndrome13,187,188 Mitochondrial disease12,13,338 mtDNA deletions12 MLL gene fusion in AML339	TOP3A inactivation produces sister chromatid exchanges, defective chromosome segregation, ultrafine anaphase bridges and mitotic catastrophy6,52,187 Resolves stalled replication forks with FANCM192	Essential for early embryogenesis184	TOP3A is essential185,186; the mitochondrial isoform is required for fertility and maintenance of mtDNA186,193	Top3 knockout causes low growth and hyper-recombination340,341 Rescued by knocking out Sgs1, the yeast RECQ orthologue342
TOP3B	Neurological disorders, intellectual deficiency and psychosis26,197 Carcinogenesis199 Premature ageing4	Genomic instability (R-loops)199 Defective neuronal synapses343 Genetically engineered TOP3B (R338W) producing irreversible TOP3Bccs induces DNA damage and R-loops2	Dispensable194–196 Splenomegaly, immune infiltrates194 and autoimmunity196 Infertility and aneuploidy195 Neurological defects198 Defective synapse formation197 Tumours	Defective synapse formation197 Defect in heterochromatin formation138
TDP1	Spinocerebellar ataxia with axonal neuropathy344,345	Knockout reduces mtDNA transcript abundance323 Deficiency causes broad sensitivity to DNA damaging agents346	Age-dependent cerebellar atrophy347 Potentiates with ATM neurodegeneration250	Reduced lifespan and climbing ability in females348	TDP1 knockout (there is no TDP2) is hyper-sensitive to TOP1ccs349,350
TDP2	Seizures, intellectual deficiency and ataxia264,351	TDP2 repairs TOP1ccs in the absence of TDP1 (refs264,352) Required for picornavirus replication353,354 Suppresses genomic instability induced by androgens and oestrogens108	Genomic instability and neuronal defects280,355 Increased incidence of thymic cancers in Atm–/– mice356

AML, acute myeloid leukaemia; ATM, ataxia telangiectasia mutated; FANCM, Fanconi anaemia group M protein; MLL, myeloid/lymphoid or mixed-lineage leukaemia; mtDNA, mitochondrial DNA; TDP, tyrosyl-DNA phosphodiesterase; TOP1, topoisomerase 1; TOP1cc, topoisomerase cleavage complex; TOP1MT, mitochondrial TOP1.