NBS1 binds directly to TOPBP1 via disparate interactions between the NBS1 BRCT1 domain and the TOPBP1 BRCT1 and BRCT2 domains

Huynh, Oanh; Ruis, Kenna; Montales, Katrina; Michael, W. Matthew

doi:10.1016/j.dnarep.2023.103461

Cited by 2 publications

References 40 publications

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Resection of DNA double-strand breaks activates Mre11–Rad50–Nbs1- and Rad9–Hus1–Rad1-dependent mechanisms that redundantly promote ATR checkpoint activation and end processing in Xenopus egg extracts

Tatsukawa,

Sakamoto,

Kawasoe

et al. 2024

Nucleic Acids Research

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Sensing and processing of DNA double-strand breaks (DSBs) are vital to genome stability. DSBs are primarily detected by the ATM checkpoint pathway, where the Mre11–Rad50–Nbs1 (MRN) complex serves as the DSB sensor. Subsequent DSB end resection activates the ATR checkpoint pathway, where replication protein A, MRN, and the Rad9–Hus1–Rad1 (9–1–1) clamp serve as the DNA structure sensors. ATR activation depends also on Topbp1, which is loaded onto DNA through multiple mechanisms. While different DNA structures elicit specific ATR-activation subpathways, the regulation and mechanisms of the ATR-activation subpathways are not fully understood. Using DNA substrates that mimic extensively resected DSBs, we show here that MRN and 9–1–1 redundantly stimulate Dna2-dependent long-range end resection and ATR activation in Xenopus egg extracts. MRN serves as the loading platform for ATM, which, in turn, stimulates Dna2- and Topbp1-loading. Nevertheless, MRN promotes Dna2-mediated end processing largely independently of ATM. 9–1–1 is dispensable for bulk Dna2 loading, and Topbp1 loading is interdependent with 9–1–1. ATR facilitates Mre11 phosphorylation and ATM dissociation. These data uncover that long-range end resection activates two redundant pathways that facilitate ATR checkpoint signaling and DNA processing in a vertebrate system.

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Resection of DNA double-strand breaks activates Mre11–Rad50–Nbs1- and Rad9–Hus1–Rad1-dependent mechanisms that redundantly promote ATR checkpoint activation and end processing in Xenopus egg extracts

Tatsukawa,

Sakamoto,

Kawasoe

et al. 2024

Nucleic Acids Research

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Unique and shared functions of the Rad9–Hus1–Rad1 and Mre11–Rad50–Nbs1 complexes in ATR checkpoint activation and long-range DNA end resection inXenopusegg extracts

Tatsukawa

Sakamoto

Kawasoe

et al. 2023

Preprint

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Sensing and processing of DNA double-strand breaks (DSBs) are vital to genome stability. DSBs are primarily detected by the ATM checkpoint pathway, where the Mre11–Rad50–Nbs1 (MRN) complex serves as the DSB sensor. Subsequent DSB end resection promotes the transition from the ATM to the ATR checkpoint pathway, where replication protein A, MRN, and the Rad9–Hus1–Rad1 (9–1–1) checkpoint clamp serve as the DNA structure sensors. 9–1–1 and MRN recruit Topbp1, a critical checkpoint mediator that activates the ATR kinase. However, how multiple sensors contribute to regulating end resection and checkpoint activation remains ambiguous. Using DNA substrates that mimic extensively resected DSBs, we show here that MRN and 9–1–1 redundantly stimulate Dna2-dependent long-range end resection and ATR activation inXenopusegg extracts. MRN serves as the loading platform for Dna2, ATM, and Topbp1. In contrast, 9–1–1 is dispensable for bulk Dna2 loading, and Topbp1 loading is interdependent with 9–1–1 in this pathway. ATR facilitates Mre11 phosphorylation and ATM dissociation. Our results delineate the molecular mechanism of and interplay between two redundant pathways that stimulate ATR checkpoint activation and long-range DSB end resection in vertebrates.

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NBS1 binds directly to TOPBP1 via disparate interactions between the NBS1 BRCT1 domain and the TOPBP1 BRCT1 and BRCT2 domains

Cited by 2 publications

References 40 publications

Resection of DNA double-strand breaks activates Mre11–Rad50–Nbs1- and Rad9–Hus1–Rad1-dependent mechanisms that redundantly promote ATR checkpoint activation and end processing in Xenopus egg extracts

Resection of DNA double-strand breaks activates Mre11–Rad50–Nbs1- and Rad9–Hus1–Rad1-dependent mechanisms that redundantly promote ATR checkpoint activation and end processing in Xenopus egg extracts

Unique and shared functions of the Rad9–Hus1–Rad1 and Mre11–Rad50–Nbs1 complexes in ATR checkpoint activation and long-range DNA end resection inXenopusegg extracts

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