TOP3A coupling with replication forks and repair of TOP3A cleavage complexes

ABSTRACT

Humans have two Type IA topoisomerases, topoisomerase IIIα (TOP3A) and topoisomerase IIIβ (TOP3B). In this review, we focus on the role of human TOP3A in DNA replication and highlight the recent progress made in understanding TOP3A in the context of replication. Like other topoisomerases, TOP3A acts by a reversible mechanism of cleavage and rejoining of DNA strands allowing changes in DNA topology. By cleaving and resealing single-stranded DNA, it generates TOP3A-linked single-strand breaks as TOP3A cleavage complexes (TOP3Accs) with a TOP3A molecule covalently bound to the 5´-end of the break. TOP3A is critical for both mitochondrial and for nuclear DNA replication. Here, we discuss the formation and repair of irreversible TOP3Accs, as their presence compromises genome integrity as they form TOP3A DNA-protein crosslinks (TOP3A-DPCs) associated with DNA breaks. We discuss the redundant pathways that repair TOP3A-DPCs, and how their defects are a source of DNA damage leading to neurological diseases and mitochondrial disorders.

KEYWORDS:

• DNA replication
• DNA repair
• TOP3Accs
• TOP3A-DPCs
• nucleus
• mitochondria

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

L.K.S and Y.P are supported by the Center for Cancer Research, the Intramural Program of the National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [Grant Z01 BC Z01 BC 006161-17 and Grant Z01 BC 006150-19].