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Mol Cell January 1, 2016; 64 (4): 688-703.

Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN.

Stingele J , Bellelli R , Alte F , Hewitt G , Sarek G , Maslen SL , Tsutakawa SE , Borg A , Kjær S , Tainer JA , Skehel JM , Groll M , Boulton SJ .

Covalent DNA-protein crosslinks (DPCs) are toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription. Little was known about DPC-specific repair mechanisms until the recent identification of a DPC-processing protease in yeast. The existence of a DPC protease in higher eukaryotes is inferred from data in Xenopus laevis egg extracts, but its identity remains elusive. Here we identify the metalloprotease SPRTN as the DPC protease acting in metazoans. Loss of SPRTN results in failure to repair DPCs and hypersensitivity to DPC-inducing agents. SPRTN accomplishes DPC processing through a unique DNA-induced protease activity, which is controlled by several sophisticated regulatory mechanisms. Cellular, biochemical, and structural studies define a DNA switch triggering its protease activity, a ubiquitin switch controlling SPRTN chromatin accessibility, and regulatory autocatalytic cleavage. Our data also provide a molecular explanation on how SPRTN deficiency causes the premature aging and cancer predisposition disorder Ruijs-Aalfs syndrome.

PubMed ID: 27871365
PMC ID: PMC5128726
Article link: Mol Cell
Grant support: [+]
Genes referenced: eif4g2 prss1 sprtn

Article Images: [+] show captions
References [+] :
Baker, Nucleotide excision repair eliminates unique DNA-protein cross-links from mammalian cells. 2007, Pubmed

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