Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

Lessel, Davor; Vaz, Bruno; Halder, Swagata; Lockhart, Paul J.; Marinović-Terzić, Ivana; López-Mosqueda, Jaime; Philipp, Melanie; Sim, Joe Chou Hung; Smith, Katherine R.; Oehler, Judith; Cabrera, Elisa; Freire, Raimundo; Pope, Kate; Nahid, Amsha; Norris, Fiona; Leventer, Richard J.; Delatycki, Martin B.; Barbi, Gotthold; Ameln, Simon von; Högel, Josef; Degoricija, Marina; Fertig, Regina; Burkhalter, Martin D.; Hofmann, Kay; Thiele, Holger; Altmüller, Janine; Nürnberg, Gudrun; Nürnberg, Peter; Bahlo, Melanie; Martin, George M.; Aalfs, Cora M.; Oshima, Junko; Terzić, Janoš; Amor, David J.; Đikić, Ivan; Ramadan, Kristijan; Kubisch, Christian

doi:10.1038/ng.3103

Cited by 184 publications

(232 citation statements)

References 45 publications

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“…Genome-wide homozygosity scores were produced by HomozygosityMapper, a Web-based approach to homozygosity mapping (58). Data handling, evaluation, and statistical analysis were previously described in detail (30). To confirm the homozygous antiterminating mutation, c.1492T>C, in MDM2, we designed primers, 5´-gagggctttgatgttcctga-´3 and 5´-ggagttggtgtaaaggatgagc-´3, and PCR amplified it by using genomic DNA from the affected individual.…”

Section: Methodsmentioning

confidence: 99%

Dysfunction of the MDM2/p53 axis is linked to premature aging

Lessel

Trujillo

et al. 2017

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 99%

Dysfunction of the MDM2/p53 axis is linked to premature aging

Lessel

Trujillo

et al. 2017

Journal of Clinical Investigation

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“…Although the importance of the UBZ and PIP domains in the targeting of Polη is clear, defects in these domains do not completely inactivate SPARTAN function. Additionally, SPARTAN has a putative protease domain (SprT), whose mutation results in serious deficiency in SPARTAN's functions in vivo [31,32]. Recently, the DNA binding and DNA dependent protease activities of WSS1 has been described, and it was suggested to be the yeast functional homologue of human Spartan, based on the domain organization they contain [33].…”

Section: Introductionmentioning

confidence: 99%

The DNA-binding box of human SPARTAN contributes to the targeting of Polη to DNA damage sites

et al. 2017

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The DNA-binding box of human SPARTAN contributes to the targeting of Pol to DNA damage sites, DNA Repair http://dx.doi.org/10.1016/j. dnarep.2016.10.007 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractInappropriate repair of UV-induced DNA damage results in human diseases such as Xeroderma pigmentosum (XP), which is associated with an extremely high risk of skin cancer. A variant form of XP is caused by the absence of Polη, which is normally able to bypass UV-induced DNA lesions in an errorfree manner. However, Polη is highly error prone when replicating undamaged DNA and, thus, the regulation of the proper targeting of Polη is crucial for the prevention of mutagenesis and UV-induced cancer formation. Spartan is a novel regulator of the damage tolerance pathway, and its association with Ub-PCNA has a role in Polη targeting; however, our knowledge about its function is only rudimentary. Here, we describe a new biochemical property of purified human SPARTAN by showing that it is a DNAbinding protein. Using a DNA binding mutant, we provide in vivo evidence that DNA binding by SPARTAN regulates the targeting of Polη to damage sites after UV exposure, and this function contributes highly to its DNA-damage tolerance function.

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“…Whether these lesions are indeed DPCs remains to be determined. Notably, SPRTN also seems to be crucial for genome stability in humans, as indicated by a recent study of three patients with mutations in the human SPRTN gene 55 . Intriguingly, one of these mutations directly affects a residue next to the protease active site of SPRTN, supporting the notion that SPRTN acts as a protease similarly to Wss1.…”

Section: Interplay Of Dpc-repair Pathwaysmentioning

confidence: 99%

DNA–protein crosslink repair

Stingele

Jentsch

2015

Nat Rev Mol Cell Biol

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DNA-protein crosslinks (DPCs) are highly toxic DNA adducts, but whether dedicated DPC-repair mechanisms exist was until recently unknown. This has changed with discoveries made in yeast and Xenopus laevis that revealed a protease-based DNA-repair pathway specific for DPCs. Importantly, mutations in the gene encoding the putative human homologue of a yeast DPC protease cause a human premature ageing and cancer predisposition syndrome. Thus, DPC repair is a previously overlooked genome-maintenance mechanism that may be essential for tumour suppression.

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Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features

Cited by 184 publications

References 45 publications

Dysfunction of the MDM2/p53 axis is linked to premature aging

Dysfunction of the MDM2/p53 axis is linked to premature aging

The DNA-binding box of human SPARTAN contributes to the targeting of Polη to DNA damage sites

DNA–protein crosslink repair

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