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DNA-dependent metalloprotease SPRTN

Definition:

DNA-dependent metalloendopeptidase that mediates the proteolytic cleavage of covalent DNA-protein cross-links (DPCs) during DNA synthesis, thereby playing a key role in maintaining genomic integrity. DPCs are highly toxic DNA lesions that interfere with essential chromatin transactions, such as replication and transcription, and which are induced by reactive agents, such as UV light or formaldehyde. Associates with the DNA replication machinery and specifically removes DPCs during DNA synthesis. Acts as a pleiotropic protease for DNA-binding proteins cross-linked with DNA, such as TOP1, TOP2A, histones H3 and H4. Mediates degradation of DPCs that are not ubiquitinated, while it is not able to degrade ubiquitinated DPCs (By similarity). SPRTN activation requires polymerase collision with DPCs followed by helicase bypass of DPCs (By similarity). Involved in recruitment of VCP/p97 to sites of DNA damage. Also acts as an activator of CHEK1 during normal DNA replication by mediating proteolytic cleavage of CHEK1, thereby promoting CHEK1 removal from chromatin and subsequent activation. Does not activate CHEK1 in response to DNA damage. May also act as a 'reader' of ubiquitinated PCNA: recruited to sites of UV damage and interacts with ubiquitinated PCNA and RAD18, the E3 ubiquitin ligase that monoubiquitinates PCNA. Facilitates chromatin association of RAD18 and is required for efficient PCNA monoubiquitination, promoting a feed-forward loop to enhance PCNA ubiquitination and translesion DNA synthesis.

References:

[1]. Yuka Machida, et al. Spartan/C1orf124 is important to prevent UV-induced mutagenesis. Cell Cycle. 2012 Sep 15;11(18):3395-402. [Content Brief]

[2]. John Fielden, et al. TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts. Nat Commun. 2020 Mar 9;11(1):1274. [Content Brief]

[3]. Emily J Davis, et al. DVC1 (C1orf124) recruits the p97 protein segregase to sites of DNA damage. Nat Struct Mol Biol. 2012 Nov;19(11):1093-100. [Content Brief]

[4]. Bruno Vaz, et al. Metalloprotease SPRTN/DVC1 Orchestrates Replication-Coupled DNA-Protein Crosslink Repair. Mol Cell. 2016 Nov 17;64(4):704-719. [Content Brief]

[5]. Faxiang Li, et al. Structural Insight into DNA-Dependent Activation of Human Metalloprotease Spartan. Cell Rep. 2019 Mar 19;26(12):3336-3346.e4. [Content Brief]

[6]. Jaime Lopez-Mosqueda, et al. SPRTN is a mammalian DNA-binding metalloprotease that resolves DNA-protein crosslinks. Elife. 2016 Nov 17;5:e21491. [Content Brief]

[7]. Swagata Halder, et al. SPRTN protease and checkpoint kinase 1 cross-activation loop safeguards DNA replication. Nat Commun. 2019 Jul 17;10(1):3142. [Content Brief]

[8]. Julian Stingele, et al. Mechanism and Regulation of DNA-Protein Crosslink Repair by the DNA-Dependent Metalloprotease SPRTN. Mol Cell. 2016 Nov 17;64(4):688-703. [Content Brief]

[9]. Richard C Centore, et al. Spartan/C1orf124, a reader of PCNA ubiquitylation and a regulator of UV-induced DNA damage response. Mol Cell. 2012 Jun 8;46(5):625-35. [Content Brief]

[10]. Gargi Ghosal, et al. Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis. J Biol Chem. 2012 Oct 5;287(41):34225-33. [Content Brief]

[11]. Jinzhou Huang, et al. Tandem Deubiquitination and Acetylation of SPRTN Promotes DNA-Protein Crosslink Repair and Protects against Aging. Mol Cell. 2020 Sep 3;79(5):824-835.e5. [Content Brief]

[12]. Szilvia Juhasz, et al. Characterization of human Spartan/C1orf124, an ubiquitin-PCNA interacting regulator of DNA damage tolerance. Nucleic Acids Res. 2012 Nov;40(21):10795-808. [Content Brief]

[13]. Anna Mosbech, et al. DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks. Nat Struct Mol Biol. 2012 Nov;19(11):1084-92. [Content Brief]

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