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Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-Linked RNA and DNA Breaks

47 Pages Posted: 12 Mar 2020 Sneak Peek Status: Review Complete

See all articles by Sourav Saha

Sourav Saha

National Institutes of Health - Developmental Therapeutics Branch

Yilun Sun

National Institutes of Health - Developmental Therapeutics Branch

Shar-Yin Huang

National Institutes of Health - Developmental Therapeutics Branch

Ukhyun Jo

National Institutes of Health - Developmental Therapeutics Branch

Hongliang Zhang

National Institutes of Health - Developmental Therapeutics Branch

Yuk-Ching Tse-Dinh

Florida International University (FIU)

Yves Pommier

National Institutes of Health - Developmental Therapeutics Branch

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Abstract

Genetic inactivation of TOP3B is linked with schizophrenia, autism, intellectual disability and cancer. The present study demonstrates that in vivo TOP3B forms both RNA and DNA cleavage complexes (TOP3Bccs) and reveals a pathway for repairing TOP3Bccs. For detecting cellular TOP3Bccs, we engineered a “self-trapping” mutant of TOP3B (R338W TOP3B) and to determine how human cells repair TOP3Bccs, we depleted tyrosyl-DNA phosphodiesterases (TDP1 and TDP2). TDP2-deficient cells produced elevated TOP3Bccs both in DNA and RNA. Conversely, overexpression of TDP2 lowered cellular TOP3Bccs. Using recombinant human TDP2, we demonstrate that TDP2 cannot excise the native form of TOP3Bccs. Hypothesizing that TDP2 cannot access phosphotyrosyl linkage unless TOP3B is either proteolyzed or denatured, we found that cellular TOP3Bccs are ubiquitinated by the E3 Ubiquitin Ligase TRIM41 before undergoing proteasomal degradation and excision by TDP2.

Keywords: Topoisomerase, TDP2, Ubiquitin-Proteasome, TRIM41, DNA repair

Suggested Citation

Saha, Sourav and Sun, Yilun and Huang, Shar-Yin and Jo, Ukhyun and Zhang, Hongliang and Tse-Dinh, Yuk-Ching and Pommier, Yves, Topoisomerase 3B (TOP3B) DNA and RNA Cleavage Complexes and Pathway to Repair TOP3B-Linked RNA and DNA Breaks. Available at SSRN: https://ssrn.com/abstract=3550241 or http://dx.doi.org/10.2139/ssrn.3550241
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Sourav Saha

National Institutes of Health - Developmental Therapeutics Branch

Building 37, Room 5068A
Bethesda, MD 20892-4264
United States

Yilun Sun

National Institutes of Health - Developmental Therapeutics Branch

Building 37, Room 5068A
Bethesda, MD 20892-4264
United States

Shar-Yin Huang

National Institutes of Health - Developmental Therapeutics Branch ( email )

Building 37, Room 5068A
Bethesda, MD 20892-4264
United States

Ukhyun Jo

National Institutes of Health - Developmental Therapeutics Branch ( email )

Building 37, Room 5068A
Bethesda, MD 20892-4264
United States

Hongliang Zhang

National Institutes of Health - Developmental Therapeutics Branch

Building 37, Room 5068A
Bethesda, MD 20892-4264
United States

Yuk-Ching Tse-Dinh

Florida International University (FIU) ( email )

University Park
11200 SW 8th Street
Miami, FL 33199
United States

Yves Pommier (Contact Author)

National Institutes of Health - Developmental Therapeutics Branch ( email )

Building 37, Room 5068A
Bethesda, MD 20892-4264
United States

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