Repair of topoisomerase 1–induced DNA damage by tyrosyl-DNA phosphodiesterase 2 (TDP2) is dependent on its magnesium binding

Shimizu, Naoto; Hamada, Y.; Morozumi, Ryosuke; Yamamoto, Junpei; Iwai, Shigenori; Sugiyama, Keiichi; Ide, Hiroshi; Tsuda, Masashi

doi:10.1016/j.jbc.2023.104988

Cited by 5 publications

References 74 publications

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Low magnesium in conjunction with high homocysteine increases DNA damage in healthy middle aged Australians

Dhillon,

Deo,

Fenech

2024

Eur J Nutr

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Purpose Magnesium is one of the most common elements in the human body and plays an important role as a cofactor of enzymes required for DNA replication and repair and many other biochemical mechanisms including sensing and regulating one-carbon metabolism deficiencies. Low intake of magnesium can increase the risk of many diseases, in particular, chronic degenerative disorders. However, its role in prevention of DNA damage has not been studied fully in humans so far. Therefore, we tested the hypothesis that magnesium deficiency either on its own or in conjunction with high homocysteine (Hcy) induces DNA damage in vivo in humans. Methods The present study was carried out in 172 healthy middle aged subjects from South Australia. Blood levels of magnesium, Hcy, folate and vitamin B12 were measured. Cytokinesis-Block Micronucleus cytome assay was performed to measure three DNA damage biomarkers: micronuclei (MN), nucleoplasmic bridges (NPBs) and nuclear buds (NBuds) in peripheral blood lymphocytes. Results Data showed that magnesium and Hcy are significantly inversely correlated with each other (r = − 0.299, p < 0.0001). Furthermore, magnesium is positively correlated both with folate (p = 0.002) and vitamin B12 (p = 0.007). Magnesium is also significantly inversely correlated with MN (p < 0.0001) and NPB (p < 0.0001). Individuals with low magnesium and high Hcy exhibited significantly higher frequency of MN and NPBs compared to those with high magnesium and low Hcy (p < 0.0001). Furthermore, there was an interactive effect between these two factors as well in inducing MN (p = 0.01) and NPB (p = 0.048). Conclusions The results obtained in the present study indicate for the first time that low in vivo levels of magnesium either on its own or in the presence of high Hcy increases DNA damage as evident by higher frequencies of MN and NPBs.

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Low magnesium in conjunction with high homocysteine increases DNA damage in healthy middle aged Australians

Dhillon,

Deo,

Fenech

2024

Eur J Nutr

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TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription

Rubio-Contreras,

Gómez-Herreros

2023

Nat Commun

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DNA topoisomerase I (TOP1) removes torsional stress by transiently cutting one DNA strand. Such cuts are rejoined by TOP1 but can occasionally become abortive generating permanent protein-linked single strand breaks (SSBs). The repair of these breaks is initiated by tyrosyl-DNA phosphodiesterase 1 (TDP1), a conserved enzyme that unlinks the TOP1 peptide from the DNA break. Additionally, some of these SSBs can result in double strand breaks (DSBs) either during replication or by a poorly understood transcription-associated process. In this study, we identify these DSBs as a source of genome rearrangements, which are suppressed by TDP1. Intriguingly, we also provide a mechanistic explanation for the formation of chromosomal translocations unveiling an error-prone pathway that relies on the MRN complex and canonical non-homologous end-joining. Collectively, these data highlight the threat posed by TOP1-induced DSBs during transcription and demonstrate the importance of TDP1-dependent end-joining in protecting both gene transcription and genome stability.

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SCAN1 mutant TDP1 blocks the repair of DSB induced by TOP1 activity during gene transcription and promotes genome reorganisations and cell death in quiescent cells

Rubio-Contreras,

Hidalgo-García,

Angulo-Jiménez

et al. 2024

Preprint

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DNA single-strand breaks (SSBs) are the most common type of DNA damage in quiescent cells, and defects in their repair can lead to hereditary neurological syndromes. A potential endogenous source of SSBs with pathogenic potential is the abortive activity of DNA topoisomerase 1 (TOP1) during transcription. Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1), is caused by the homozygous mutation H493R in the gene encoding tyrosyl-DNA phosphodiesterase 1 (TDP1), an enzyme that initiates the repair of TOP1-induced SSBs by unlinking the TOP1 peptide from the break end. Notably, transcription-associated TOP1-induced SSBs can be converted into DNA double strand breaks (DSBs) in quiescent cells, with TDP1 also initiating the repair of these breaks. However, the role of TOP1-induced DSBs in the pathology of SCAN1 remains unclear. In this study, we have addressed the impact that SCAN1/H493R mutation, has in the repair of TOP1-induced DSB in quiescent cells. Here we demonstrate that while TDP1 deficiency delays the repair of these breaks, TDP1H493Rcompletely blocks it. This blockage is accompanied by prolonged covalent trapping of TDP1H493Rto DNA and results in genome instability and increased cell death in quiescent cells. We also demonstrate that tyrosyl-DNA phosphodiesterase 2 (TDP2) can backup TDP1 loss but not SCAN1 TDP1H493Rmutation. Intriguingly, we also unveil that a mutation in catalytic H263 results in a negative dominant effect on TOP1-induced DSB repair. Collectively, our data provide novel insights into the molecular etiology of SCAN1 and support the potential of TOP1-induced DSBs as a main contributor to hereditary neurological syndromes.

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Repair of topoisomerase 1–induced DNA damage by tyrosyl-DNA phosphodiesterase 2 (TDP2) is dependent on its magnesium binding

Cited by 5 publications

References 74 publications

Low magnesium in conjunction with high homocysteine increases DNA damage in healthy middle aged Australians

Low magnesium in conjunction with high homocysteine increases DNA damage in healthy middle aged Australians

TDP1 suppresses chromosomal translocations and cell death induced by abortive TOP1 activity during gene transcription

SCAN1 mutant TDP1 blocks the repair of DSB induced by TOP1 activity during gene transcription and promotes genome reorganisations and cell death in quiescent cells

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