Human Topoisomerases and Their Roles in Genome Stability and Organization

Overview

Journal Nat Rev Mol Cell Biol

Specialties Cell Biology
Molecular Biology

Date 2022 Mar 1

PMID 35228717

Authors

Yves Pommier

Andre Nussenzweig

Shunichi Takeda

Caroline Austin

Affiliations

Soon will be listed here.

Abstract

Human topoisomerases comprise a family of six enzymes: two type IB (TOP1 and mitochondrial TOP1 (TOP1MT), two type IIA (TOP2A and TOP2B) and two type IA (TOP3A and TOP3B) topoisomerases. In this Review, we discuss their biochemistry and their roles in transcription, DNA replication and chromatin remodelling, and highlight the recent progress made in understanding TOP3A and TOP3B. Because of recent advances in elucidating the high-order organization of the genome through chromatin loops and topologically associating domains (TADs), we integrate the functions of topoisomerases with genome organization. We also discuss the physiological and pathological formation of irreversible topoisomerase cleavage complexes (TOPccs) as they generate topoisomerase DNA-protein crosslinks (TOP-DPCs) coupled with DNA breaks. We discuss the expanding number of redundant pathways that repair TOP-DPCs, and the defects in those pathways, which are increasingly recognized as source of genomic damage leading to neurological diseases and cancer.

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References

Pommier Y, Sun Y, Huang S, Nitiss J . Roles of eukaryotic topoisomerases in transcription, replication and genomic stability. Nat Rev Mol Cell Biol. 2016; 17(11):703-721. PMC: 9248348. DOI: 10.1038/nrm.2016.111. View

Saha S, Sun Y, Huang S, Baechler S, Pongor L, Agama K . DNA and RNA Cleavage Complexes and Repair Pathway for TOP3B RNA- and DNA-Protein Crosslinks. Cell Rep. 2020; 33(13):108569. PMC: 7859927. DOI: 10.1016/j.celrep.2020.108569. View

Capranico G, Marinello J, Chillemi G . Type I DNA Topoisomerases. J Med Chem. 2017; 60(6):2169-2192. DOI: 10.1021/acs.jmedchem.6b00966. View

Bizard A, Hickson I . The many lives of type IA topoisomerases. J Biol Chem. 2020; 295(20):7138-7153. PMC: 7242696. DOI: 10.1074/jbc.REV120.008286. View

Dyson S, Segura J, Martinez-Garcia B, Valdes A, Roca J . Condensin minimizes topoisomerase II-mediated entanglements of DNA in vivo. EMBO J. 2020; 40(1):e105393. PMC: 7780148. DOI: 10.15252/embj.2020105393. View

Valdes A, Segura J, Dyson S, Martinez-Garcia B, Roca J . DNA knots occur in intracellular chromatin. Nucleic Acids Res. 2017; 46(2):650-660. PMC: 5778459. DOI: 10.1093/nar/gkx1137. View

Griffith J, NASH H . Genetic rearrangement of DNA induces knots with a unique topology: implications for the mechanism of synapsis and crossing-over. Proc Natl Acad Sci U S A. 1985; 82(10):3124-8. PMC: 397727. DOI: 10.1073/pnas.82.10.3124. View

Nicholls T, Nadalutti C, Motori E, Sommerville E, Gorman G, Basu S . Topoisomerase 3α Is Required for Decatenation and Segregation of Human mtDNA. Mol Cell. 2018; 69(1):9-23.e6. PMC: 5935120. DOI: 10.1016/j.molcel.2017.11.033. View

Ahmad M, Xue Y, Lee S, Martindale J, Shen W, Li W . RNA topoisomerase is prevalent in all domains of life and associates with polyribosomes in animals. Nucleic Acids Res. 2016; 44(13):6335-49. PMC: 4994864. DOI: 10.1093/nar/gkw508. View

10.

Ahmad M, Xu D, Wang W . Type IA topoisomerases can be "magicians" for both DNA and RNA in all domains of life. RNA Biol. 2017; 14(7):854-864. PMC: 5546716. DOI: 10.1080/15476286.2017.1330741. View

12.

Vann K, Oviatt A, Osheroff N . Topoisomerase II Poisons: Converting Essential Enzymes into Molecular Scissors. Biochemistry. 2021; 60(21):1630-1641. PMC: 8209676. DOI: 10.1021/acs.biochem.1c00240. View

13.

Champoux J . DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001; 70:369-413. DOI: 10.1146/annurev.biochem.70.1.369. View

14.

Yang W . Topoisomerases and site-specific recombinases: similarities in structure and mechanism. Crit Rev Biochem Mol Biol. 2010; 45(6):520-34. PMC: 6290911. DOI: 10.3109/10409238.2010.513375. View

15.

Seol Y, Zhang H, Pommier Y, Neuman K . A kinetic clutch governs religation by type IB topoisomerases and determines camptothecin sensitivity. Proc Natl Acad Sci U S A. 2012; 109(40):16125-30. PMC: 3479559. DOI: 10.1073/pnas.1206480109. View

16.

Stewart L, Redinbo M, Qiu X, Hol W, Champoux J . A model for the mechanism of human topoisomerase I. Science. 1998; 279(5356):1534-41. DOI: 10.1126/science.279.5356.1534. View

17.

Salceda J, Fernandez X, Roca J . Topoisomerase II, not topoisomerase I, is the proficient relaxase of nucleosomal DNA. EMBO J. 2006; 25(11):2575-83. PMC: 1478187. DOI: 10.1038/sj.emboj.7601142. View

18.

Champoux J . Evidence for an intermediate with a single-strand break in the reaction catalyzed by the DNA untwisting enzyme. Proc Natl Acad Sci U S A. 1976; 73(10):3488-91. PMC: 431141. DOI: 10.1073/pnas.73.10.3488. View

19.

Woessner R, Mattern M, Mirabelli C, Johnson R, Drake F . Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ. 1991; 2(4):209-14. View

20.

McClendon A, Rodriguez A, Osheroff N . Human topoisomerase IIalpha rapidly relaxes positively supercoiled DNA: implications for enzyme action ahead of replication forks. J Biol Chem. 2005; 280(47):39337-45. DOI: 10.1074/jbc.M503320200. View

21.

Stoll G, Pietilainen O, Linder B, Suvisaari J, Brosi C, Hennah W . Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders. Nat Neurosci. 2013; 16(9):1228-1237. PMC: 3986889. DOI: 10.1038/nn.3484. View