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Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability

Author

Listed:
  • Hao-Lian Wang

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Yan Chen

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Yun-Qian Wang

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • En-Wei Tao

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Juan Tan

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Qian-Qian Liu

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Chun-Min Li

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Xue-Mei Tong

    (Shanghai Jiao Tong University School of Medicine)

  • Qin-Yan Gao

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Jie Hong

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Ying-Xuan Chen

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

  • Jing-Yuan Fang

    (Renji Hospital, School of Medicine, Shanghai Jiao Tong University)

Abstract

In our previous study, we reported that sirtuin5 (SIRT5), a member of the NAD+-dependent class III histone deacetylase family, is highly expressed in colorectal cancer (CRC). Herein we show that SIRT5 knockdown impairs the production of ribose-5-phosphate, which is essential for nucleotide synthesis, resulting in continuous and irreparable DNA damage and consequently leading to cell cycle arrest and enhanced apoptosis in CRC cells. These SIRT5 silencing-induced effects can be reversed by nucleoside supplementation. Mechanistically, SIRT5 activates transketolase (TKT), a key enzyme in the non-oxidative pentose phosphate pathway, in a demalonylation-dependent manner. Furthermore, TKT is essential for SIRT5-induced malignant phenotypes of CRC both in vivo and in vitro. Altogether, SIRT5 silencing induces DNA damage in CRC via post-translational modifications and inhibits tumor growth, suggesting that SIRT5 can serve as a promising target for CRC treatment.

Suggested Citation

  • Hao-Lian Wang & Yan Chen & Yun-Qian Wang & En-Wei Tao & Juan Tan & Qian-Qian Liu & Chun-Min Li & Xue-Mei Tong & Qin-Yan Gao & Jie Hong & Ying-Xuan Chen & Jing-Yuan Fang, 2022. "Sirtuin5 protects colorectal cancer from DNA damage by keeping nucleotide availability," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33903-8
    DOI: 10.1038/s41467-022-33903-8
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    References listed on IDEAS

    as
    1. Yun-Qian Wang & Hao-Lian Wang & Jie Xu & Juan Tan & Lin-Na Fu & Ji-Lin Wang & Tian-Hui Zou & Dan-Feng Sun & Qin-Yan Gao & Ying-Xuan Chen & Jing-Yuan Fang, 2018. "Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    2. Lei Li & Lan Shi & Shangda Yang & Ruorong Yan & Di Zhang & Jianguo Yang & Lin He & Wanjin Li & Xia Yi & Luyang Sun & Jing Liang & Zhongyi Cheng & Lei Shi & Yongfeng Shang & Wenhua Yu, 2016. "SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability," Nature Communications, Nature, vol. 7(1), pages 1-17, November.
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