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Remodeling of Interstrand Crosslink Proximal Replisomes Is Dependent on ATR, FANCM, and FANCD2.

Cell Rep. 2019 May 07;27(6):1794-1808.e5
Jing Huang 1 , Jing Zhang 2 , Marina A Bellani 2 , Durga Pokharel 2 , Julia Gichimu 2 , Ryan C James 2 , Himabindu Gali 3 , Chen Ling 4 , Zhijiang Yan 5 , Dongyi Xu 6 , Junjie Chen 7 , Amom Ruhikanta Meetei 8 , Lei Li 7 , Weidong Wang 4 , Michael M Seidman 9
Jing Huang 1 , Jing Zhang 2 , Marina A Bellani 2 , Durga Pokharel 2 , Julia Gichimu 2 , Ryan C James 2 , Himabindu Gali 3 , Chen Ling 4 , Zhijiang Yan 5 , Dongyi Xu 6 , Junjie Chen 7 , Amom Ruhikanta Meetei 8 , Lei Li 7 , Weidong Wang 4 , Michael M Seidman 9
+ et al

[No authors listed]

Author information
  • 1 Institute of Chemical Biology and Nanomedicine, State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Biology, Hunan University, Changsha 410082, China. Electronic address: huangjing16@hnu.edu.cn.
  • 2 Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
  • 3 Department of Pharmacology & Experimental Therapeutics and Medicine, Boston University School of Medicine, 72 East Concord St., K-712D, Boston, MA 02118-2526.
  • 4 Laboratory of Genetics and Genomics, National Institute on Aging, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA.
  • 5 Institute of DNA Repair Diseases, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China.
  • 6 Peking University, Beijing 100871, China.
  • 7 Department Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77225-0334, USA.
  • 8 Division of Experimental Hematology and Cancer Biology and Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
  • 9 Laboratory of Molecular Gerontology, National Institute on Aging, NIH, 251 Bayview Blvd., Baltimore, MD 21224, USA. Electronic address: seidmanm@grc.nia.nih.gov.

摘要

Eukaryotic replisomes are driven by the mini chromosome maintenance (MCM [M]) helicase complex, an offset ring locked around the template for leading strand synthesis by CDC45 (C) and GINS (G) proteins. Although the CDC45 MCM GINS (CMG) structure implies that interstrand crosslinks (ICLs) are absolute blocks to replisomes, recent studies indicate that cells can restart DNA synthesis on the side of the ICL distal to the initial encounter. Here, we report that restart requires ATR and is promoted by FANCD2 and phosphorylated FANCM. Following introduction of genomic ICLs and dependent on ATR and FANCD2 but not on the Fanconi anemia core proteins or FAAP24, FANCM binds the replisome complex, with concomitant release of the GINS proteins. In situ analysis of replisomes proximal to ICLs confirms the ATR-dependent release of GINS proteins while CDC45 is retained on the remodeled replisome. The results demonstrate the plasticity of CMG composition in response to replication stress.

KEYWORDS: ATR, CMG, FANCD2, FANCM, GINS, ICL, interstrand crosslink, replication traverse

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