The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Polyubiquitination of proliferating cell nuclear antigen by HLTF and SHPRH prevents genomic instability from stalled replication forks.
Open accessAbstract
Chronic stalling of DNA replication forks caused by DNA damage can lead to genomic instability. Cells have evolved lesion bypass pathways such as postreplication repair (PRR) to resolve these arrested forks. In yeast, one branch of PRR involves proliferating cell nuclear antigen (PCNA) polyubiquitination mediated by the Rad5-Ubc13-Mms2 complex that allows bypass of DNA lesion by a template-switching mechanism. Previously, we identified human SHPRH as a functional homologue of yeast Rad5 and revealed the existence of RAD5-like pathway in human cells. Here we report the identification of HLTF as a second RAD5 homologue in human cells. HLTF, like SHPRH, shares a unique domain architecture with Rad5 and promotes lysine 63-linked polyubiquitination of PCNA. Similar to yeast Rad5, HLTF is able to interact with UBC13 and PCNA, as well as SHPRH; and the reduction of either SHPRH or HLTF expression enhances spontaneous mutagenesis. Moreover, Hltf-deficient mouse embryonic fibroblasts show elevated chromosome breaks and fusions after methyl methane sulfonate treatment. Our results suggest that HLTF and SHPRH are functional homologues of yeast Rad5 that cooperatively mediate PCNA polyubiquitination and maintain genomic stability.
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“In template switching, the monoubiquitin moiety added to K164 of PCNA is instead further ubiquitinated by the HLTF E3 ubiquitin ligase, to form a K63-linked ubiquitin chain (Motegi et al., 2008; Unk et al., 2008).”
From USP7 Is a Master Regulator of Genome Stability (2020) · cites this paper as Motegi et al., 2008
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Citations
Cites
PCNA, the Maestro of the Replication Fork
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The XPV (xeroderma pigmentosum variant) gene encodes human DNA polymerase η
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Control of spontaneous and damage-induced mutagenesis by SUMO and ubiquitin conjugation
Stelter, P., & Ulrich, H. D. (2003) · Nature · doi:10.1038/nature01965 · Cited by 850
Interaction of Human DNA Polymerase η with Monoubiquitinated PCNA
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Identification of multiple distinct Snf2 subfamilies with conserved structural motifs
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SUMO-modified PCNA recruits Srs2 to prevent recombination during S phase
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Regulation of monoubiquitinated PCNA by DUB autocleavage
Huang, T. T., Nijman, S. M. B., Mirchandani, K. D., Galardy, P. J., Cohn, M. A., Haas, W., Gygi, S. P., Ploegh, H. L., Bernards, R., & D’Andrea, A. D. (2006) · Nature Cell Biology · doi:10.1038/ncb1378 · Cited by 597
The novel functions of ubiquitination in signaling
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Translesion synthesis: Y-family polymerases and the polymerase switch
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Human Fanconi anemia monoubiquitination pathway promotes homologous DNA repair
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“To determine whether SHPRH and HLTF are involved in HR, we used a recombination reporter assay (DR-GFP reporter assay), which can measure the frequency of HR between tandem GFP repeats with inactivating mutations (25).”
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Items 301–304 of 304
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Yang, X., Ding, Z., Pengwang, Y., Wei, Y., Yan, B., Xiong, W., Feng, Y., Gao, Y., & Cheng, H. (2026) · Pathology - Research and Practice · doi:10.1016/j.prp.2026.156625
Kusumoto-Matsuo, R., Masuda, Y., Kanao, R., Iwai, S., & Masutani, C. (2026) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2026.113555
Mass Spectrometry-Based Identification of Post-Translational Modifications (PTMs) of Proteins
Arshad, A., Bruno, P. S., Njoku, V., Jayaweera, T. M., Wormwood, K. L., Woods, A. G., Darie, C. C., & Aslebagh, R. (2026) · Advances in experimental medicine and biology · doi:10.1007/978-3-032-29437-1_26
Metadata
- Authors
- Motegi, A., Liaw, H.-J., Lee, K.-Y., Roest, H. P., Maas, A., Wu, X., Moinova, H., Markowitz, S. D., Ding, H., Hoeijmakers, J. H. J., & Myung, K.
- Affiliations
- National Institutes of Health (US)
- *Genome Instability Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892;
- Erasmus MC (NL)
- University of Manitoba (CA)
- Case Western Reserve University (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-08-26
- Volume
- 105
- Issue
- 34
- Pages
- 12411-12416
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2518831
- OpenAlex
- W2113224775
- Cited by
- 304
- References
- 36
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 10 · 2023: 14 · 2022: 16 · 2021: 32 · 2020: 24 · 2019: 19 · 2018: 19 · 2017: 14 · 2016: 20 · 2015: 12 · 2014: 13 · 2013: 15 · 2012: 19
- FWCI
- 7.41
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion)
- Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- HLTF, proliferating cell nuclear antigen, replication fork stalling, postreplication repair, Ubc13, genomic instability, spontaneous mutagenesis, methyl methanesulfonate, DNA damage response
- MeSH terms
- Adenosine Triphosphatases, DNA Damage, DNA Replication, DNA Helicases, DNA-Binding Proteins, Humans, Transcription Factors, Proliferating Cell Nuclear Antigen, Polyubiquitin, Saccharomyces cerevisiae Proteins, Structural Homology, Protein, Genomic Instability, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination
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