Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity.
DNA damage recognition subunits such as DDB2 and XPC protect the human skin from ultraviolet (UV) light-induced genome instability and cancer, as demonstrated by the devastating inherited syndrome xeroderma pigmentosum. Here we show that the beneficial DNA repair response triggered by these two genome caretakers critically depends on a dynamic spatiotemporal regulation of their homeostasis. The prolonged retention of DDB2 and XPC in chromatin, because of a failure to readily remove both recognition subunits by the ubiquitin-dependent p97/VCP/Cdc48 segregase complex, leads to impaired DNA excision repair of UV lesions. Surprisingly, the ensuing chromosomal aberrations in p97-deficient cells are alleviated by a concomitant downregulation of DDB2 or XPC. Also, genome instability resulting from an excess of DDB2 persisting in UV-irradiated cells is prevented by concurrent p97 overexpression. Our findings demonstrate that DNA damage sensors and repair initiators acquire unexpected genotoxic properties if not controlled by timely extraction from chromatin.
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich CH-8057, Switzerland.
Marjo-Riitta
MR
Puumalainen
Institute of Human Genetics, University of Ulm, Ulm D-89081, Germany.
Davor
D
Lessel
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich CH-8057, Switzerland.
Peter
P
Rüthemann
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich CH-8057, Switzerland.
Nina
N
Kaczmarek
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich CH-8057, Switzerland.
Karin
K
Bachmann
1] Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich CH-8057, Switzerland [2] Department of Oncology, CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford OX3 7DQ, UK.
Kristijan
K
Ramadan
Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse, Zürich CH-8057, Switzerland.
Hanspeter
H
Naegeli
D002843:Chromatin / Q000378:metabolism*; D003001:Cloning, Molecular; D003114:Colony-Forming Units Assay; D004249:DNA Damage / Q000502:physiology*; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D042822:Genomic Instability / Q000235:genetics / Q000502:physiology; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D008856:Microscopy, Fluorescence; D034741:RNA, Small Interfering / Q000235:genetics; D014466:Ultraviolet Rays
D002843:Chromatin; C117669:DDB2 protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; C086984:XPC protein, human