2. Academic Validation
  3. Inactivation of ribosomal protein S27-like impairs DNA interstrand cross-link repair by destabilization of FANCD2 and FANCI

Inactivation of ribosomal protein S27-like impairs DNA interstrand cross-link repair by destabilization of FANCD2 and FANCI

  • Cell Death Dis. 2020 Oct 13;11(10):852. doi: 10.1038/s41419-020-03082-9.
Siyuan Sun 1,  Hengqian He 1,  Yuanyuan Ma 2,  Jie Xu 3,  Guoan Chen 4,  Yi Sun 1,  Xiufang Xiong 5
Affiliations

Affiliations

  • 1 Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China.
  • 2 Shanghai Institute of Precision Medicine, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 3 Department of Urology, the Second Affiliated Hospital, Third Military Medical University (Army Medical University), Chongqing, P. R. China.
  • 4 School of Medicine, Southern University of Science and Technology, Shenzhen, Guangdong, P. R. China.
  • 5 Cancer Institute of the Second Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P. R. China. [email protected].
PMID: 33051438 DOI: 10.1038/s41419-020-03082-9
Abstract

Ribosomal protein S27-like (RPS27L), an evolutionarily conserved ribosomal protein and a direct p53 target, plays an important role in maintenance of genome integrity. We have previously reported that RPS27L regulates radiation sensitivity via the MDM2-p53 and MDM2-MRN-ATM axes. Whether and how RPS27L modulates DNA interstrand cross-link (ICL) repair is unknown. Here we identified that RPS27L binds to FANCD2 and FANCI, two Fanconi anemia (FA) proteins functioning in ICL repair pathway. Upon RPS27L knockdown, the levels of FANCD2 and FANCI are reduced due to accelerated degradation via p62-mediated autophagy-lysosome pathway, which is abrogated by chloroquine (CQ) treatment or Beclin 1 knockdown. Biologically, RPS27L knockdown suppresses FANCD2 foci formation and impairs ICL repair upon exposure to ICL-inducing agent mitomycin C (MMC) in lung Cancer cells. This effect of MMC sensitization can be partially reversed by CQ treatment. Together, our study shows that RPS27L positively regulates ICL repair by binding with FANCD2 and FANCI to prevent their degradation via autophagy-lysosome system.

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