2. Academic Validation
  3. Transient HR enhancement by RAD51-stimulatory compound confers protection on intestinal rather than hematopoietic tissue against irradiation in mice

Transient HR enhancement by RAD51-stimulatory compound confers protection on intestinal rather than hematopoietic tissue against irradiation in mice

  • DNA Repair (Amst). 2024 Dec:144:103781. doi: 10.1016/j.dnarep.2024.103781.
Zhiyu Lu 1,  Dong Chen 2,  Ning Zhang 2,  Zhiyuan Zheng 2,  Zimo Zhou 2,  Guochen Liu 2,  Jiawei An 2,  Yong Wang 3,  Yongping Su 2,  Wensheng Chen 4,  Fengchao Wang 5
Affiliations

Affiliations

  • 1 Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital) to Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 2 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 3 Department of Laboratory Animal Science, College of Basic Medical Sciences, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 4 Department of Gastroenterology, the First Affiliated Hospital (Southwest Hospital) to Army Medical University (Third Military Medical University), Chongqing, 400038, China. Electronic address: wenshengchen@hotmail.com.
  • 5 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Army Medical University (Third Military Medical University), Chongqing 400038, China. Electronic address: fengchao.w@foxmail.com.
PMID: 39520854 DOI: 10.1016/j.dnarep.2024.103781
Abstract

DNA double-strand breaks (DSBs) are cytotoxic lesions that compromise genomic integrity and trigger cell death. Homologous recombination (HR) is a major pathway for repairing DSBs in cycling cells. However, it remains unclear whether transient modulation of HR could confer protection to adult stem cells against lethal irradiation exposure. In this study, we investigated the radio-protective effect of the RAD51-stimulatory compound RS-1 on adult stem cells and progenitor cells with varying cycling rates in intestinal and hematopoietic tissues. Treatment with RS-1 even at high doses did not induce noticeable cell death or proliferation of intestinal crypt cells in vivo. Pretreatment with RS-1 before irradiation significantly decreased mitotic death, promoted DNA repair and enhanced the survival of intestinal stem cells and progenitor cells and increased the number of regenerative crypt colonies thereby mitigating IR-induced gastrointestinal syndrome. Moreover, RS-1 pretreatment could increase the survival and regeneration of irradiated intestinal organoids in vitro, which can be rescued by RAD51 Inhibitor. However, pretreatment with RS-1 in vivo did not elevate nucleated cell count or HSPCs in bone marrow after 6 Gy irradiation. Additionally, there was no impact on mouse survival due to drug treatment observed. Thus, our data suggest that targeting HR as a strategy to prevent tissue damage from acute irradiation exposure may depend on cell cycling rates and intrinsic DNA repair mechanisms.

Keywords

Hematopoietic stem cell; Homologous recombination; Intestinal stem cells; RAD51.

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