And‐1 coordinates with Claspin for efficient Chk1 activation in response to replication stress |
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| Authors: | Jing Hao Christelle de Renty Yongming Li Haijie Xiao Michael G Kemp Zhiyong Han Melvin L DePamphilis Wenge Zhu |
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| Affiliation: | 1. Department of Biochemistry and Molecular Medicine, The George Washington University Medical School, Washington, DC, USA;2. National Institute of Child Health and Human Development, Bethesda, MD, USA;3. Department of Biological Sciences, Florida Institute of Technology, Melbourne, FL, USA |
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| Abstract: | The replisome is important for DNA replication checkpoint activation, but how specific components of the replisome coordinate with ATR to activate Chk1 in human cells remains largely unknown. Here, we demonstrate that And‐1, a replisome component, acts together with ATR to activate Chk1. And‐1 is phosphorylated at T826 by ATR following replication stress, and this phosphorylation is required for And‐1 to accumulate at the damage sites, where And‐1 promotes the interaction between Claspin and Chk1, thereby stimulating efficient Chk1 activation by ATR. Significantly, And‐1 binds directly to ssDNA and facilitates the association of Claspin with ssDNA. Furthermore, And‐1 associates with replication forks and is required for the recovery of stalled forks. These studies establish a novel ATR–And‐1 axis as an important regulator for efficient Chk1 activation and reveal a novel mechanism of how the replisome regulates the replication checkpoint and genomic stability. |
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| Keywords: | And‐1 ATR Chk1 Claspin replication stress |
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