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Regulation of TDP2 functions by SUMO interactions

AuthorsLieberman, Jenna Ariel
AdvisorCortés-Ledesma, Felipe
Issue Date2017
PublisherUniversidad de Sevilla
AbstractTopoisomerase 2 (TOP2) performs a vital enzymatic activity, solving DNA topological problems in fundamental metabolic processes. The enzyme is able to untangle DNA by passing an intact helix through a transient double-strand break (DSB). The intermediate of its catalytic cycle, TOP2 covalently bound to DNA, is usually short lived, and is known as the TOP2 cleavage complex (TOP2cc). Tyrosyl DNA phosphodiesterase 2 (TDP2) is a protein involved in the removal of proteasome degraded TOP2cc, thus im-portant for the efficient repair of TOP2-induced DNA DSBs. Consequently, TDP2-deficient cells are sensitive to the TOP2 poison etoposide. Sumoylation is an important modification involved in the DNA damage response (DDR). While TOP2 sumoylation is important in several cellular processes, it is not known whether TOP2 is sumoylated in the context of the cleavage complex and the possible physiological relevance. In this work, Here, we describe for the first time SUMO1 and SUMO2/3 modification of TOP2 in the context of the cleavage complex. We imply a role for the novel TDP2 split-SIM in the preferential removal of SUMO modified TOP2cc. In order to identify pos-sible interactors involved in this process, we performed a BioID screening and identify the novel SUMO E3 ligase ZNF451, along with potential TDP2 involvement in novel processes. Through a BioID screening, we identify possible new TDP2 interactors and TDP2 involvement in novel processes. We discover a novel pathway for the repair of TOP2cc independent of known proteasomal pathways, and imply a role of the novel SUMO E3 ligase ZNF451. We suggest a role for the novel TDP2 split-SIM in the pref-erential removal of SUMO modified TOP2cc. Additionally, we find evidence for a TDP2 and proteasome independent role for ZNF451 in the repair of TOP2 double-strand breaks (DSBs).
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