Mre11 Is Essential for the Removal of Lethal Topoisomerase 2 Covalent Cleavage Complexes

Hoa, Nguyen Ngoc; Shimizu, T.; Zhou, Zhong-Wei; Wang, Zhao Qi; Deshpande, Rajashree A.; Paull, Tanya T.; Akter, Salma; Tsuda, Masashi; Furuta, Ryohei; Tsutsui, Ken; Takeda, Shunichi; Sasanuma, Hiroyuki

doi:10.1016/j.molcel.2016.11.028

Cited by 57 publications

(72 citation statements)

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“…The incisions made by hMRN are 15-20 nt from the occluded end and require all components of the complex, as well as ATP. hMRN endonucleolytic activity is also essential in vivo, as evidenced by the requirement for Mre11 nuclease activity in maintenance of cell viability (Buis et al, 2008) and for the removal of topoisomerase II covalent complexes in vertebrate cells (Hoa et al, 2016) and in Xenopus extracts (Aparicio et al, 2016). Moreover, accumulation of topoisomerase II covalent complexes was observed in NBS patient cell lines, which are deficient in full-length Nbs1 protein (Hoa et al, 2016), emphasizing the role of Nbs1 in 5 0 adduct removal, consistent with our results.…”

Section: Discussionsupporting

confidence: 90%

“…hMRN endonucleolytic activity is also essential in vivo, as evidenced by the requirement for Mre11 nuclease activity in maintenance of cell viability (Buis et al, 2008) and for the removal of topoisomerase II covalent complexes in vertebrate cells (Hoa et al, 2016) and in Xenopus extracts (Aparicio et al, 2016). Moreover, accumulation of topoisomerase II covalent complexes was observed in NBS patient cell lines, which are deficient in full-length Nbs1 protein (Hoa et al, 2016), emphasizing the role of Nbs1 in 5 0 adduct removal, consistent with our results. It is important to note that the requirements for MRN(X) endonucleolytic processing of dsDNA containing a blocked end are distinct from Mre11 endonucleolytic cutting of hairpin DNA or circular single-stranded phage DNA, which is ATP independent and can even be observed in the absence of Rad50 (Paull and Gellert, 1999;Trujillo and Sung, 2001).…”

Section: Discussionsupporting

confidence: 90%

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Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts

et al. 2016

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The human Mre11/Rad50/Nbs1 (hMRN) complex is critical for the sensing, processing, and signaling of DNA double-strand breaks. The nuclease activity of Mre11 is essential for mammalian development and cell viability, although the regulation and substrate specificity of Mre11 have been difficult to define. Here we show that hMRN catalyzes sequential endonucleolytic and exonucleolytic activities on both 5' and 3' strands of DNA ends containing protein adducts, and that Nbs1, ATP, and adducts are essential for this function. In contrast, Nbs1 inhibits Mre11/Rad50-catalyzed 3'-to-5' exonucleolytic degradation of clean DNA ends. The hMRN endonucleolytic cleavage events are further stimulated by the phosphorylated form of the human C-terminal binding protein-interacting protein (CtIP) DNA repair enzyme, establishing a role for CtIP in regulating hMRN activity. These results illuminate the important role of Nbs1 and CtIP in determining the substrates and consequences of human Mre11/Rad50 nuclease activities on protein-DNA lesions.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 90%

Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts

et al. 2016

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“…Specifically, MRE11 exhibits 3 ′ -5 ′ exonuclease and singlestranded and DNA hairpin endonuclease activities (Paull and Gellert, 1998;Trujillo et al, 2003;Lisby et al, 2004;Stracker and Petrini, 2011;Williams et al, 2011). Endonucleolytic cleavage may be of particular importance for DNA ends covalentlybound to Spo11 (Neale et al, 2005), terminated by hairpins (Lobachev et al, 2002) or generated by TOP1 and 2 poisons (Hartsuiker et al, 2009;Quennet et al, 2011;Hoa et al, 2016). Furthermore, recent in vitro studies described that NBS1 is essential to promote MRE11 nuclease activities on DNA ends containing protein adducts, while it inhibits MRE11 3 ′ to 5 ′ exonuclease degradation of clean ends .…”

Section: Nucleases In Nhejmentioning

confidence: 99%

“An End to a Means”: How DNA-End Structure Shapes the Double-Strand Break Repair Process

Serrano-Benítez

Cortés‐Ledesma

Ruiz

2020

Front. Mol. Biosci.

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Endogenously-arising DNA double-strand breaks (DSBs) rarely harbor canonical 5 ′ -phosphate, 3 ′ -hydroxyl moieties at the ends, which are, regardless of the pathway used, ultimately required for their repair. Cells are therefore endowed with a wide variety of enzymes that can deal with these chemical and structural variations and guarantee the formation of ligatable termini. An important distinction is whether the ends are directly "unblocked" by specific enzymatic activities without affecting the integrity of the DNA molecule and its sequence, or whether they are "processed" by unspecific nucleases that remove nucleotides from the termini. DNA end structure and configuration, therefore, shape the repair process, its requirements, and, importantly, its final outcome. Thus, the molecular mechanisms that coordinate and integrate the cellular response to blocked DSBs, although still largely unexplored, can be particularly relevant for maintaining genome integrity and avoiding malignant transformation and cancer.

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“…TOP2-linked DSBs can also be repaired by HR. This process requires MRN complex to initiate DNA resection and remove TOP2-linked DNA, allowing EXO1 and DNA2 to further resect the DNA [16,17]. Therefore, TDP2dependent NHEJ pathway and MRN complex-dependent HR pathway function in parallel to repair TOP2-linked DSBs.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, TDP2dependent NHEJ pathway and MRN complex-dependent HR pathway function in parallel to repair TOP2-linked DSBs. Accordingly, MRE11 inactivation is synergistic to TDP2 loss regarding their effects on cellular sensitivity to etoposide [16].…”

Section: Introductionmentioning

confidence: 99%

NBS1 is required for SPO11-linked DNA double-strand break repair in male meiosis

Zhang

Tang

et al. 2020

Cell Death Differ

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DNA double-strand breaks (DSBs) pose a serious threat to genomic stability. Paradoxically, hundreds of programed DSBs are generated by SPO11 in meiotic prophase, which are exclusively repaired by homologous recombination (HR) to promote obligate crossover between homologous chromosomes. In somatic cells, MRE11-RAD50-NBS1 (MRN) complex-dependent DNA end resection is a prerequisite for HR repair, especially for DSBs that are covalently linked with proteins or chemicals. Interestingly, all meiotic DSBs are linked with SPO11 after being generated. Although MRN complex's function in meiotic DSB repair has been established in lower organisms, the role of MRN complex in mammalian meiotic DSB repair is not clear. Here, we show that MRN complex is essential for repairing meiotic SPO11-linked DSBs in male mice. In male germ cells, conditional inactivation of NBS1, a key component of MRN complex, causes dramatic reduction of DNA end resection and defective HR repair in meiotic prophase. NBS1 loss severely disrupts chromosome synapsis, generates abnormal chromosome structures, and eventually leads to meiotic arrest and male infertility in mice. Unlike in somatic cells, the recruitment of NBS1 to SPO11-linked DSB sites is MDC1-independent but requires other phosphorylated proteins. Collectively, our study not only reveals the significance of MRN complex in repairing meiotic DSBs but also discovers a unique mechanism that recruits MRN complex to SPO11-linked DSB sites.

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Mre11 Is Essential for the Removal of Lethal Topoisomerase 2 Covalent Cleavage Complexes

Cited by 57 publications

References 0 publications

Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts

Nbs1 Converts the Human Mre11/Rad50 Nuclease Complex into an Endo/Exonuclease Machine Specific for Protein-DNA Adducts

“An End to a Means”: How DNA-End Structure Shapes the Double-Strand Break Repair Process

NBS1 is required for SPO11-linked DNA double-strand break repair in male meiosis

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