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.

Deregulation of ribosomal proteins in human cancers

“…RPS27L has been shown to directly bind to two proteins involved in DNA interstrand cross-link repair, FANCD2 and FANCI which protect them from degradation in lung cancer cells. The KD of RPS27L abrogates the level of FANCD2 and FANCI which sensitizes the cells to mitomycin C treatment reducing cell viability and colony formation [133]. These results indicate that the effects of RPs on lung cancer are dependent on the types of cancer and the different pathways through which these proteins are involved.…”

“…RPS27L has been shown to directly bind to two proteins involved in DNA interstrand cross-link repair, FANCD2 and FANCI, which protect them from degradation in lung cancer cells. The KD of RPS27L abrogates the level of FANCD2 and FANCI which sensitizes the cells to mitomycin C treatment reducing cell viability and colony formation [ 133 ].…”

Ribosome Biogenesis and Cancer: Overview on Ribosomal Proteins

“…More recently, it has been reported that in lung cancer cells, RPS27L physically binds Fanconi anemia group D2 (FANCD2) and Fanconi anemia group I (FANCI), two proteins involved in DNA damage and repair. The inactivation of RPS27L impairs DNA interstrand cross-link repair by promoting the degradation of FANCD2 and FNCI through the p62-mediated autophagy-lysosome pathway [ 64 ].…”

Focal Point of Fanconi Anemia Signaling

“…FANCI forms a heterodimer with FANCD2 upon DNA damage and protects the deubiquitination of FANCD2 to better clamp DNA together. In addition to monoubiquitination and deubiquitination of FANCD2 and FANCI controlled by the FA core complex and USP1, respectively [ 18 , 20 , 21 ], this dynamic balance can also be regulated by a ribosomal protein S27-like which connects p53 signaling [ 55 , 56 ]. Ribosomal protein S27-like (RPS27L), a direct p53 target, plays an important role in the maintenance of genome integrity [ 57 , 58 , 59 , 60 ].…”

“…RPS27L was found to bind to FANCD2 and FANCI to prevent their degradation via the autophagy–lysosome system. Conversely, its inactivation impairs FA signaling by destabilization of the FANCD2 and FANCI/the ID complexes [ 55 ]. Here, RPS27L is an evolutionarily conserved ribosomal protein, distinct from the commonly known proteins for DDR.…”