Helicase-Like Transcription Factor HLTF and E3 Ubiquitin Ligase SHPRH Confer DNA Damage Tolerance through Direct Interactions with Proliferating Cell Nuclear Antigen (PCNA).

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

DNA Damage/*physiology ; DNA Helicases/*metabolism ; DNA-Binding Proteins/*metabolism ; Proliferating Cell Nuclear Antigen/*metabolism ; Transcription Factors/*metabolism ; Ubiquitin-Protein Ligases/*metabolism; DNA/metabolism ; DNA Helicases/genetics ; DNA Replication/physiology ; DNA-Binding Proteins/genetics ; Genomic Instability ; HEK293 Cells ; Humans ; Mutation ; Transcription Factors/genetics ; Ubiquitin ; Ubiquitin-Protein Ligases/genetics ; Ultraviolet Rays

To prevent replication fork collapse and genome instability under replicative stress, DNA damage tolerance (DDT) mechanisms have evolved. The RAD5 homologs, HLTF (helicase-like transcription factor) and SHPRH (SNF2, histone-linker, PHD and RING finger domain-containing helicase), both ubiquitin ligases, are involved in several DDT mechanisms; DNA translesion synthesis (TLS), fork reversal/remodeling and template switch (TS). Here we show that these two human RAD5 homologs contain functional APIM PCNA interacting motifs. Our results show that both the role of HLTF in TLS in HLTF overexpressing cells, and nuclear localization of SHPRH, are dependent on interaction of HLTF and SHPRH with PCNA. Additionally, we detected multiple changes in the mutation spectra when APIM in overexpressed HLTF or SHPRH were mutated compared to overexpressed wild type proteins. In plasmids from cells overexpressing the APIM mutant version of HLTF, we observed a decrease in C to T transitions, the most common mutation caused by UV irradiation, and an increase in mutations on the transcribed strand. These results strongly suggest that direct binding of HLTF and SHPRH to PCNA is vital for their function in DDT.
Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Keywords: APIM; DNA damage tolerance (DDT); RAD5; Translesion synthesis (TLS); mutagenicity

0 (DNA-Binding Proteins)
0 (HLTF protein, human)
0 (Proliferating Cell Nuclear Antigen)
0 (Transcription Factors)
0 (Ubiquitin)
9007-49-2 (DNA)
EC 2.3.2.27 (SHPRH protein, human)
EC 2.3.2.27 (Ubiquitin-Protein Ligases)
EC 3.6.4.- (DNA Helicases)

Date Created: 20200125 Date Completed: 20201112 Latest Revision: 20201112

20231215

PMC7037221

10.3390/ijms21030693

31973093