Rad5, HLTF, and SHPRH: A Fresh View of an Old Story

Elserafy, Menattallah; Abugable, Arwa A.; Atteya, Reham; El‐Khamisy, Sherif F.

doi:10.1016/j.tig.2018.04.006

Cited by 20 publications

(16 citation statements)

References 13 publications

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“…reduced requirement for SGS1 , Figure 4D), and cluster along with several RAD5 mutant alleles that have a weak effect on function (Figure 4C—Intermediate cluster). Among this group is the rad5 G535R —a mutation adjacent to the SNF2 Walker A motif that is present in the original W303 laboratory strain (65,66). Strikingly, when we truncate the RAD5 N-terminus up to the HIRAN domain ( N164Δ ) we observe no effect on the interaction profile, but when we further truncate beyond the HIRAN domain ( N293Δ ), or delete just the HIRAN domain ( 173–281Δ ), we see near complete elimination of all 25 RAD5 OE genetic interactions (Figure 4C—Vector cluster).…”

Section: Resultsmentioning

confidence: 99%

Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability

Bryant

Šunjevarić

Berchowitz

et al. 2019

Nucleic Acids Research

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The postreplication repair gene, HLTF, is often amplified and overexpressed in cancer. Here we model HLTF dysregulation through the functionally conserved Saccharomyces cerevisiae ortholog, RAD5. Genetic interaction profiling and landscape enrichment analysis of RAD5 overexpression (RAD5OE) reveals requirements for genes involved in recombination, crossover resolution, and DNA replication. While RAD5OE and rad5Δ both cause cisplatin sensitivity and share many genetic interactions, RAD5OE specifically requires crossover resolving genes and drives recombination in a region of repetitive DNA. Remarkably, RAD5OE induced recombination does not require other post-replication repair pathway members, or the PCNA modification sites involved in regulation of this pathway. Instead, the RAD5OE phenotype depends on a conserved domain necessary for binding 3′ DNA ends. Analysis of DNA replication intermediates supports a model in which dysregulated Rad5 causes aberrant template switching at replication forks. The direct effect of Rad5 on replication forks in vivo, increased recombination, and cisplatin sensitivity predicts similar consequences for dysregulated HLTF in cancer.

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Section: Resultsmentioning

confidence: 99%

Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability

Bryant

Šunjevarić

Berchowitz

et al. 2019

Nucleic Acids Research

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“…Another issue is the complex interplay between overlapping DDR and DDT pathways that would limit the onset of novel somatic mutations. In this context, interference with MMS2/Ubc13/HLTF may favor TLS by reducing template switching [60].…”

Section: Discussionmentioning

confidence: 99%

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

Brossel

Fontaine

Hoyos

et al. 2021

Cancers

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Immunotherapy based on two checkpoint inhibitors (ICI), programmed cell death 1 (PD-1, Nivolumab) and cytotoxic T-lymphocyte 4 (CTLA-4, Ipilimumab), has provided a significant improvement in overall survival for malignant mesothelioma (MM). Despite this major breakthrough, the median overall survival of patients treated with the two ICIs only reached 18.1 months vs. 14 months in standard chemotherapy. With an objective response rate of 40%, only a subset of patients benefits from immunotherapy. A critical step in the success of immunotherapy is the presentation of tumor-derived peptides by the major histocompatibility complex I (MHC-I) of tumor cells. These neoantigens are potentially immunogenic and trigger immune responses orchestrated by cytotoxic cells. In MM, tumor development is nevertheless characterized by a low mutation rate despite major structural chromosomal rearrangements driving oncogenesis (BAP1, NF2, CDKN2AB). In this opinion, we propose to investigate an approach based on the mechanisms of the DNA damage tolerance (DDT) pathways to increase the frequency of non-synonymous mutations. The idea is to transiently activate the error-prone DDT in order to generate neoantigens while preserving a fully competent antitumor immune response.

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“…HLTF is a transcriptional factor involved in the regulation of various biological processes. Defects in HLTF and SHPRH are associated with diseases ( Elserafy et al, 2018 ). HLTF regulates the embryonic and postnatal development of heart and brain in mice and regulation of Clock-Controlled Genes ( Elserafy et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

“…Defects in HLTF and SHPRH are associated with diseases ( Elserafy et al, 2018 ). HLTF regulates the embryonic and postnatal development of heart and brain in mice and regulation of Clock-Controlled Genes ( Elserafy et al, 2018 ). Both HLTF and SHPRH were found to be down-regulated in several cancer types ( Elserafy et al, 2018 ) and HLTF is also up-regulated in various cancer types ( Bryant et al, 2019 ).…”

Section: Discussionmentioning

confidence: 99%

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance

et al. 2021

Self Cite

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Ribonucleoside monophosphate (rNMP) incorporation in genomic DNA poses a significant threat to genomic integrity. In addition to repair, DNA damage tolerance mechanisms ensure replication progression upon encountering unrepaired lesions. One player in the tolerance mechanism is Rad5, which is an E3 ubiquitin ligase and helicase. Here, we report a new role for yeast Rad5 in tolerating rNMP incorporation, in the absence of the bona fide ribonucleotide excision repair pathway via RNase H2. This role of Rad5 is further highlighted after replication stress induced by hydroxyurea or by increasing rNMP genomic burden using a mutant DNA polymerase (Pol ε - Pol2-M644G). We further demonstrate the importance of the ATPase and ubiquitin ligase domains of Rad5 in rNMP tolerance. These findings suggest a similar role for the human Rad5 homologues helicase-like transcription factor (HLTF) and SNF2 Histone Linker PHD RING Helicase (SHPRH) in rNMP tolerance, which may impact the response of cancer cells to replication stress-inducing therapeutics.

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Rad5, HLTF, and SHPRH: A Fresh View of an Old Story

Cited by 20 publications

References 13 publications

Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability

Rad5 dysregulation drives hyperactive recombination at replication forks resulting in cisplatin sensitivity and genome instability

Activation of DNA Damage Tolerance Pathways May Improve Immunotherapy of Mesothelioma

A role for Rad5 in ribonucleoside monophosphate (rNMP) tolerance

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