Proliferating Cell Nuclear Antigen (PCNA)-binding Protein C1orf124 Is a Regulator of Translesion Synthesis

Ghosal, Gargi; Leung, Justin; Nair, Binoj C.; Fong, Ka Wing; Chen, Junjie

doi:10.1074/jbc.m112.400135

Cited by 94 publications

(132 citation statements)

References 40 publications

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“…We mapped the DNA-binding box in the SPARTAN sequence and generated a point mutant SPARTAN that was partially defective in DNA binding. Previously, we and others described that the ubiquitylation of PCNA regulates the subnuclear targeting of SPARTAN [24][25][26]28]. We demonstrate that the DNA binding of SPARTAN is not essential for its intranuclear distribution.…”

Section: Resultsmentioning

confidence: 44%

“…Previously, we and others have shown that SPARTAN plays a critical role in the regulation of targeting Polη, in which the binding of Ub-PCNA via its PIP and UBZ domains is very important [26][27][28]. In parallel, it has been proposed that -besides Ub-PCNA binding -another targeting mechanism could be present by which SPARTAN regulates damage bypass [25,26,32]. Therefore, we tested how the DNA binding of SPARTAN affects Polη foci formation.…”

Section: Dna Binding Is Essential For the Dna Repair Function Of Spartanmentioning

confidence: 99%

“…We and others have described previously that Spartan has an important function at the stalled replication fork in the targeting of Polη to the site of DNA damage induced by UV irradiation [24][25][26][27][28]. Since it has also been suggested that Spartan is the human homologue of yeast WSS1, which is a DNAdependent protease [33], we decided to test whether SPARTAN can bind DNA and whether this biochemical activity affects its function after UV damage.…”

Section: Spartan Binds Single-stranded Dna and Replication Fork-likementioning

confidence: 99%

“…The targeting of SPARTAN to the stalled replication fork depends mainly on its PCNA-interacting (PIP) and ubiquitin-binding zinc finger (UBZ) domains, which can mediate its interaction with Ub-PCNA. Additionally, SPARTAN plays an important role in the correct targeting of Polη to the stalled replication fork; in its absence, UV-induced Polη foci formation is highly defective [24][25][26][27][28]. Other publications suggest that SPARTAN is responsible for the targeting of p97 (VCP, vasolinecontaining protein), which is an ATP-dependent segregase and facilitates the dissociation of Polη from the site of action [29,30].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 44%

Section: Dna Binding Is Essential For the Dna Repair Function Of Spartanmentioning

confidence: 99%

Section: Spartan Binds Single-stranded Dna and Replication Fork-likementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2017

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“…This situation may trigger recombination-dependent repair, e.g., by break-induced replication (BIR), though with the risk of genomic rearrangements (GCRs). the precise role of Dvc1/Spartan remains highly controversial despite recent efforts (Centore et al, 2012;Davis et al, 2012;Ghosal et al, 2012;Juhasz et al, 2012;Kim et al, 2013;Machida et al, 2012;Mosbech et al, 2012;Vaz et al, 2013). Some studies suggested that Dvc1/Spartan plays a role in conjunction with Cdc48/p97 in removal of Polh from chromatin, but the significance of Dvc1/Spartan's protease domain remained unsolved (Davis et al, 2012;Mosbech et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

A DNA-Dependent Protease Involved in DNA-Protein Crosslink Repair

Stingele

Schwarz

Bloemeke

et al. 2014

Cell

240

391

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Toxic DNA-protein crosslinks (DPCs) arise by ionizing irradiation and UV light, are particularly caused by endogenously produced reactive compounds such as formaldehyde, and also occur during compromised topoisomerase action. Although nucleotide excision repair and homologous recombination contribute to cell survival upon DPCs, hardly anything is known about mechanisms that target the protein component of DPCs directly. Here, we identify the metalloprotease Wss1 as being crucial for cell survival upon exposure to formaldehyde and topoisomerase 1-dependent DNA damage. Yeast mutants lacking Wss1 accumulate DPCs and exhibit gross chromosomal rearrangements. Notably, in vitro assays indicate that substrates such as topoisomerase 1 are processed by the metalloprotease directly and in a DNA-dependent manner. Thus, our data suggest that Wss1 contributes to survival of DPC-harboring cells by acting on DPCs proteolytically. We propose that DPC proteolysis enables repair of these unique lesions via downstream canonical DNA repair pathways.

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Regulation of translesion DNA synthesis in mammalian cells

Tang

Guo

2020

Environ and Mol Mutagen

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The genomes of all living cells are under endogenous and exogenous attacks every day, causing diverse genomic lesions. Most of the lesions can be timely repaired by multiple DNA repair pathways. However, some may persist during S‐phase, block DNA replication, and challenge genome integrity. Eukaryotic cells have evolved DNA damage tolerance (DDT) to mitigate the lethal effects of arrested DNA replication without prior removal of the offending DNA damage. As one important mode of DDT, translesion DNA synthesis (TLS) utilizes multiple low‐fidelity DNA polymerases to incorporate nucleotides opposite DNA lesions to maintain genome integrity. Three different mechanisms have been proposed to regulate the polymerase switching between high‐fidelity DNA polymerases in the replicative machinery and one or more specialized enzymes. Additionally, it is known that proliferating cell nuclear antigen (PCNA) mono‐ubiquitination is essential for optimal TLS. Given its error‐prone property, TLS is closely associated with spontaneous and drug‐induced mutations in cells, which can potentially lead to tumorigenesis and chemotherapy resistance. Therefore, TLS process must be tightly modulated to avoid unwanted mutagenesis. In this review, we will focus on polymerase switching and PCNA mono‐ubiquitination, the two key events in TLS pathway in mammalian cells, and summarize current understandings of regulation of TLS process at the levels of protein–protein interactions, post‐translational modifications as well as transcription and noncoding RNAs. Environ. Mol. Mutagen. 61:680–692, 2020. © 2020 Wiley Periodicals, Inc.

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Proliferating Cell Nuclear Antigen (PCNA)-binding Protein C1orf124 Is a Regulator of Translesion Synthesis

Cited by 94 publications

References 40 publications

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

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

A DNA-Dependent Protease Involved in DNA-Protein Crosslink Repair

Regulation of translesion DNA synthesis in mammalian cells

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