Chromatin retention of DNA damage sensors DDB2 and XPC through loss of p97 segregase causes genotoxicity

• Published in: Nature communications Vol. 5; no. 1; p. 3695
• Main Authors: Puumalainen, Marjo-Riitta, Lessel, Davor, Rüthemann, Peter, Kaczmarek, Nina, Bachmann, Karin, Ramadan, Kristijan, Naegeli, Hanspeter
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28.04.2014; Nature Publishing Group
• Subjects: 13/106; 13/51; 14; 14/1; 14/19; 14/34; 631/208/211; 631/337/1427/2566; 82; Chromatin - metabolism; Cloning, Molecular; Colony-Forming Units Assay; DNA damage; DNA Damage - physiology; DNA Primers - genetics; DNA repair; DNA Repair - physiology; DNA-Binding Proteins - metabolism; Genomes; Genomic Instability - genetics; Genomic Instability - physiology; HEK293 Cells; HeLa Cells; Humanities and Social Sciences; Humans; Immunoblotting; Kinases; Microscopy, Fluorescence; multidisciplinary; Oncology; Proteins; Retention; RNA polymerase; RNA, Small Interfering - genetics; Science; Science (multidisciplinary); Sensors; Ultraviolet radiation; Ultraviolet Rays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4695

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. Nucleotide excision repair protects the genome from UV light-induced damage. Here, Puumalainen et al . show that chromatin retention of the UV lesion sensors DDB2 and XPC due to a lack of p97 segregase impairs excision repair, revealing that DNA lesion-associated protein homeostasis affects genome stability.