| Autor: |
Kelliher, Jessica L., Folkerts, Melissa L., Shen, Kaiyuan V., Song, Wan, Tengler, Kyle, Stiefel, Clara M., Lee, Seong-Ok, Dray, Eloise, Zhao, Weixing, Koss, Brian, Pannunzio, Nicholas R., Leung, Justin W. |
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| Zdroj: |
Nature Communications; 5/31/2024, Vol. 15 Issue 1, p1-14, 14p |
| Abstrakt: |
The master DNA damage repair histone protein, H2AX, is essential for orchestrating the recruitment of downstream mediator and effector proteins at damaged chromatin. The phosphorylation of H2AX at S139, γH2AX, is well-studied for its DNA repair function. However, the extended C-terminal tail is not characterized. Here, we define the minimal motif on H2AX for the canonical function in activating the MDC1-RNF8-RNF168 phosphorylation-ubiquitination pathway that is important for recruiting repair proteins, such as 53BP1 and BRCA1. Interestingly, H2AX recruits 53BP1 independently from the MDC1-RNF8-RNF168 pathway through its evolved C-terminal linker region with S139 phosphorylation. Mechanistically, 53BP1 recruitment to damaged chromatin is mediated by the interaction between the H2AX C-terminal tail and the 53BP1 Oligomerization-Tudor domains. Moreover, γH2AX-linker mediated 53BP1 recruitment leads to camptothecin resistance in H2AX knockout cells. Overall, our study uncovers an evolved mechanism within the H2AX C-terminal tail for regulating DNA repair proteins at damaged chromatin. Histone H2AX is a central regulator in DNA repair. Here, the authors show that the H2AX C-terminal linker mediates recruitment of 53BP1, a mechanism which evolved to function independently of the canonical phospho-ubiquitin axis important for DNA repair regulation. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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