2. Academic Validation
  3. The regulation loop of MARVELD1 interacting with PARP1 in DNA damage response maintains genome stability and promotes therapy resistance of cancer cells

The regulation loop of MARVELD1 interacting with PARP1 in DNA damage response maintains genome stability and promotes therapy resistance of cancer cells

  • Cell Death Differ. 2023 Feb 7. doi: 10.1038/s41418-023-01118-z.
Haoxiu Sun # 1,  Chao Liu # 2 3 4 5,  Fang Han # 1,  Xiaoyu Lin 1,  Liangyu Cao 1,  Chenxing Liu 1,  Qiuyu Ji 1,  Jinjin Cui 1,  Yuanfei Yao 2 3 4 5,  Bojun Wang 2 3 4 5,  Yuanyu Liao 2 3 4 5,  Huan Nie 6,  Yanqiao Zhang 7 8 9 10,  Yu Li 11
Affiliations

Affiliations

  • 1 School of Life Science and Technology, Harbin Institute of Technology, Harbin, China.
  • 2 Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China.
  • 3 Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China.
  • 4 Key Laboratories of Tumor Immunology in Heilongjiang, Harbin, China.
  • 5 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China.
  • 6 School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. nh1212@hit.edu.cn.
  • 7 Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, China. yanqiaozhang@ems.hrbmu.edu.cn.
  • 8 Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China. yanqiaozhang@ems.hrbmu.edu.cn.
  • 9 Key Laboratories of Tumor Immunology in Heilongjiang, Harbin, China. yanqiaozhang@ems.hrbmu.edu.cn.
  • 10 Translational Medicine Research and Cooperation Center of Northern China, Heilongjiang Academy of Medical Sciences, Harbin, China. yanqiaozhang@ems.hrbmu.edu.cn.
  • 11 School of Life Science and Technology, Harbin Institute of Technology, Harbin, China. liyugene@hit.edu.cn.
  • # Contributed equally.
PMID: 36750717 DOI: 10.1038/s41418-023-01118-z
Abstract

The DNA damage response (DDR) plays crucial roles in Cancer prevention and therapy. Poly(ADP-ribose) polymerase 1 (PARP1) mediates multiple signal transduction in the DDR as a master regulator. Uncovering the regulatory factors of PARP1 contributes to a more comprehensive view of tumorigenesis and treatment strategies. Here, we reveal that MARVELD1 acts as a mediator of DDR to perform early events and maintain genome stability. Mechanistically, PARP1 PARylates MARVELD1 at D102, D118 and D130, and in turn, MARVELD1 stabilizes PARP1 by enhancing NAA50-mediated acetylation, thus forming a positive feedback loop. MARVELD1 knockout mice and their embryo fibroblasts exhibit genomic instability and shorter half-life of PARP1. Moreover, MARVELD1 partnering with PARP1 facilitates resistance to genotoxic drugs and disrupts PARP Inhibitor (PARPi) effect in PDX model of colorectal Cancer (CRC). Overall, our results underline the link between MARVELD1 and PARP1 in therapeutic resistance based on DDR and provide new insights for clinical tumor therapy of PARPi.

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