ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress

Su Hyung Park, Nalae Kang, Eunho Song, Minwoo Wie, Eun A. Lee, Sunyoung Hwang, Deokjae Lee, Jae Sun Ra, In Bae Park, Jieun Park, Sukhyun Kang, Jun Hong Park, Sungchul Hohng, Kyoo-young Lee () and Kyungjae Myung ()
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Su Hyung Park: Institute for Basic Science
Nalae Kang: Institute for Basic Science
Eunho Song: Seoul National University
Minwoo Wie: Ulsan National Institute of Science and Technology
Eun A. Lee: Institute for Basic Science
Sunyoung Hwang: Institute for Basic Science
Deokjae Lee: Ulsan National Institute of Science and Technology
Jae Sun Ra: Institute for Basic Science
In Bae Park: Institute for Basic Science
Jieun Park: Institute for Basic Science
Sukhyun Kang: Institute for Basic Science
Jun Hong Park: Institute for Basic Science
Sungchul Hohng: Seoul National University
Kyoo-young Lee: Institute for Basic Science
Kyungjae Myung: Institute for Basic Science

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract Maintaining stability of replication forks is important for genomic integrity. However, it is not clear how replisome proteins contribute to fork stability under replication stress. Here, we report that ATAD5, a PCNA unloader, plays multiple functions at stalled forks including promoting its restart. ATAD5 depletion increases genomic instability upon hydroxyurea treatment in cultured cells and mice. ATAD5 recruits RAD51 to stalled forks in an ATR kinase-dependent manner by hydroxyurea-enhanced protein-protein interactions and timely removes PCNA from stalled forks for RAD51 recruitment. Consistent with the role of RAD51 in fork regression, ATAD5 depletion inhibits slowdown of fork progression and native 5-bromo-2ʹ-deoxyuridine signal induced by hydroxyurea. Single-molecule FRET showed that PCNA itself acts as a mechanical barrier to fork regression. Consequently, DNA breaks required for fork restart are reduced by ATAD5 depletion. Collectively, our results suggest an important role of ATAD5 in maintaining genome integrity during replication stress.

Date: 2019
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DOI: 10.1038/s41467-019-13667-4

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