期刊
DNA REPAIR
卷 21, 期 -, 页码 1-11出版社
ELSEVIER
DOI: 10.1016/j.dnarep.2014.05.001
关键词
DNA damage response; Checkpoint control; DNA replication; DNA repair; Protein-protein interactions
资金
- KAKENHI [22770172]
- Uehara Memorial Foundation [103-2012]
- Japan Society for the Promotion of Science [11J04189]
- Grants-in-Aid for Scientific Research [22770172, 11J04189] Funding Source: KAKEN
The checkpoint clamp Rad9-Hus1-Rad1 (9-1-1) interacts with TopBP1 via two casein kinase 2 (CK2)-phosphorylation sites, Ser-341 and Ser-387 in Rad9. While this interaction is known to be important for the activation of ATR-Chk1 pathway, how the interaction contributes to their accumulation at sites of DNA damage remains controversial. Here, we have studied the contribution of the 9-1-1 /TopBP1 interaction to the assembly and activation of checkpoint proteins at damaged DNA. UV-irradiation enhanced association of Rad9 with chromatin and its localization to sites of DNA damage without a direct interaction with TopBP1. TopBP1, as well as RPA and Rad17 facilitated Rad9 recruitment to DNA damage sites. Similar to Rad9, TopBP1 also localized to sites of UV-induced DNA damage. The DNA damage-induced TopBP1 redistribution was delayed in cells expressing a TopBP1 binding-deficient Rad9 mutant. Pharmacological inhibition of ATR recapitulated the delayed accumulation of TopBP1 in the cells, suggesting that ATR activation will induce more efficient accumulation of T0pBP1. Taken together, T0pBP1 and Rad9 can be independently recruited to damaged DNA. Once recruited, a direct interaction of 9-1-1/TopBP1 occurs and induces ATR activation leading to further TopBP1 accumulation and amplification of the checkpoint signal. Thus, we propose a new positive feedback mechanism that is necessary for successful formation of the damage-sensing complex and DNA damage checkpoint signaling in human cells. (C) 2014 Elsevier B.V. All rights reserved.
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