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

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.

• Authors: Siyuan Sun, Hengqian He, Yuanyuan Ma, Jie Xu, Guoan Chen, Yi Sun, Xiufang Xiong
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 10 Pg. 852 (10 13 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 33051438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• FANCD2 protein, human
• FANCI protein, human
• Fanconi Anemia Complementation Group D2 Protein
• Fanconi Anemia Complementation Group Proteins
• RPS27L protein, human
• Ribosomal Proteins

Topics

• A549 Cells
• DNA Damage
• DNA Repair
• Fanconi Anemia Complementation Group D2 Protein (genetics, metabolism)
• Fanconi Anemia Complementation Group Proteins (genetics, metabolism)
• HEK293 Cells
• Humans
• Lysosomes (metabolism)
• Ribosomal Proteins (genetics, metabolism)
• Transfection