2. Academic Validation
  3. ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress

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

  • Nat Commun. 2019 Dec 16;10(1):5718. doi: 10.1038/s41467-019-13667-4.
Su Hyung Park 1,  Nalae Kang 1,  Eunho Song 2 3,  Minwoo Wie 4,  Eun A Lee 1,  Sunyoung Hwang 1,  Deokjae Lee 4 5,  Jae Sun Ra 1,  In Bae Park 1,  Jieun Park 1,  Sukhyun Kang 1,  Jun Hong Park 1,  Sungchul Hohng 2 3 6,  Kyoo-Young Lee 7,  Kyungjae Myung 8 9
Affiliations

Affiliations

  • 1 Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea.
  • 2 Interdisciplinary Graduate Program in Biophysics and Chemical Biology, Seoul National University, Seoul, 08826, Republic of Korea.
  • 3 Institute of Applied Physics, Seoul National University, Seoul, 08826, Republic of Korea.
  • 4 Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea.
  • 5 Medytox Inc. 114, Yeongtong-gu, Suwon-si, Gyeonggi-do, Korea.
  • 6 Department of Physics and Astronomy, Seoul National University, Seoul, 08826, Republic of Korea.
  • 7 Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea. klee2910@ibs.re.kr.
  • 8 Center for Genomic Integrity, Institute for Basic Science, Ulsan, Korea. kmyung@ibs.re.kr.
  • 9 Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea. kmyung@ibs.re.kr.
PMID: 31844045 DOI: 10.1038/s41467-019-13667-4
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-2'-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.

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