title: A new pathway that regulates 53BP1 stability implicates cathepsin L and vitamin D in DNA repair.
abstract: Genomic instability due to telomere dysfunction and defective repair of DNA double-strand breaks (DSBs) is an underlying cause of ageing-related diseases. 53BP1 is a key factor in DNA DSBs repair and its deficiency is associated with genomic instability and cancer progression. Here, we uncover a novel pathway regulating the stability of 53BP1. We demonstrate an unprecedented role for the cysteine protease Cathepsin L (CTSL) in the degradation of 53BP1. Overexpression of CTSL in wild-type fibroblasts leads to decreased 53BP1 protein levels and changes in its cellular distribution, resulting in defective repair of DNA DSBs. Importantly, we show that the defects in DNA repair associated with 53BP1 deficiency upon loss of A-type lamins are due to upregulation of CTSL. Furthermore, we demonstrate that treatment with vitamin D stabilizes 53BP1 and promotes DNA DSBs repair via inhibition of CTSL, providing an as yet unsuspected link between vitamin D action and DNA repair. Given that CTSL upregulation is a hallmark of cancer and progeria, regulation of this pathway could be of great therapeutic significance for these diseases.
authors.affiliation: Radiation and Cancer Biology Division, Department of Radiation Oncology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Gonzalez-Suarez
authors.forename: Abena B
authors.initials: AB
authors.lastname: Redwood
authors.forename: David A
authors.initials: DA
authors.lastname: Grotsky
authors.forename: Martin A
authors.initials: MA
authors.lastname: Neumann
authors.forename: Emily H-Y
authors.initials: EH
authors.lastname: Cheng
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Adriana
authors.initials: A
authors.lastname: Dusso
authors.forename: Susana
authors.initials: S
authors.lastname: Gonzalo
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology; D056668:Cathepsin L / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004792:Enzyme Precursors / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013045:Species Specificity; D014162:Transfection; D000071857:Tumor Suppressor p53-Binding Protein 1; D014807:Vitamin D / Q000502:physiology*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D004792:Enzyme Precursors; D034904:Lamin Type A; D007976:Leupeptins; D011993:Recombinant Fusion Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D014807:Vitamin D; C534281:CTSL protein, human; D056668:Cathepsin L; C534278:Ctsl protein, mouse; D046988:Proteasome Endopeptidase Complex; D002117:Calcitriol; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde