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

Marjo-Riitta Puumalainen, Davor Lessel, Peter Rüthemann, Nina Kaczmarek, Karin Bachmann, Kristijan Ramadan () and Hanspeter Naegeli ()
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Marjo-Riitta Puumalainen: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse
Davor Lessel: Institute of Human Genetics, University of Ulm
Peter Rüthemann: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse
Nina Kaczmarek: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse
Karin Bachmann: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse
Kristijan Ramadan: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse
Hanspeter Naegeli: Institute of Pharmacology and Toxicology, University of Zürich-Vetsuisse

Nature Communications, 2014, vol. 5, issue 1, 1-10

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4695

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