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Nucleic Acids Res 2024 Apr 12;526:3146-3163. doi: 10.1093/nar/gkae082.
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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 K , Sakamoto R , Kawasoe Y , Kubota Y , Tsurimoto T , Takahashi TS , Ohashi E .

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.

PubMed ID: 38349040
PMC ID: PMC11014350
Article link: Nucleic Acids Res
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: atm atr chek1 dna2 exo1 hus1 mre11 msh2 nbn nr2e1 orc2 rad1 rad50 rad9a rbbp8 rfc1 rps3a topbp1

Article Images: [+] show captions
References [+] :
Blackford, ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. 2017, Pubmed