Molecular basis for damage recognition and verification by XPC-RAD23B and TFIIH in nucleotide excision repair

Mu, Hong; Geacintov, Nicholas E.; Broyde, Suse; Yeo, Jung Eun; Schärer, Orlando D.

doi:10.1016/j.dnarep.2018.08.005

Cited by 61 publications

(72 citation statements)

References 115 publications

(144 reference statements)

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“…Previously, it was shown that tethering DDB2 to chromatin recruits XPC but never TFIIH, whereas tethering XPC recruits TFIIH but never DDB2, implying that DDB2 and TFIIH associate with XPC on DNA damage in a mutually exclusive manner 63 . Furthermore, the superimposition of the crystal structures of DDB2 and yeast XPC/Rad4 bound to DNA indicates that the two proteins cannot stably bind the same lesion simultaneously, as both interact with the DNA minor groove around the lesion 10,11,15,56 . However, lesion-bound CRL4 DDB2 is required for XPC ubiquitylation 23 , arguing that DDB2 and XPC should-temporarily-coexist, prior to the handover of the damage to the XPC-TFIIH verification complex.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair

et al. 2020

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DNA damage sensors DDB2 and XPC initiate global genome nucleotide excision repair (NER) to protect DNA from mutagenesis caused by helix-distorting lesions. XPC recognizes helical distortions by binding to unpaired ssDNA opposite DNA lesions. DDB2 binds to UV-induced lesions directly and facilitates efficient recognition by XPC. We show that not only lesion-binding but also timely DDB2 dissociation is required for DNA damage handover to XPC and swift progression of the multistep repair reaction. DNA-binding-induced DDB2 ubiquitylation and ensuing degradation regulate its homeostasis to prevent excessive lesion (re)binding. Additionally, damage handover from DDB2 to XPC coincides with the arrival of the TFIIH complex, which further promotes DDB2 dissociation and formation of a stable XPC-TFIIH damage verification complex. Our results reveal a reciprocal coordination between DNA damage recognition and verification within NER and illustrate that timely repair factor dissociation is vital for correct spatiotemporal control of a multistep repair process.

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Section: Discussionmentioning

confidence: 99%

Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair

et al. 2020

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“…12,13 UV-DDB is believed to hand off cyclobutane pyrimidine dimer (CPD) lesions to XPC. 2 This essential lesion recognition role of XPC has been well established by experimental studies, which have shown that XPC binding is required for the subsequent binding of the TFIIH complex. 1,14−16 The XPD helicase in TFIIH verifies the lesion.…”

Section: Introductionmentioning

confidence: 92%

“…In TC-NER, recognition is accomplished by a stalled RNA polymerase II. In GG-NER, the current focus, recognition is carried out by the XPC-RAD23B complex, 2 aided in cells by centrin 2 11 and UV-DDB for UV photo lesions. 12,13 UV-DDB is believed to hand off cyclobutane pyrimidine dimer (CPD) lesions to XPC.…”

Section: Introductionmentioning

confidence: 99%

Lesion Sensing during Initial Binding by Yeast XPC/Rad4: Toward Predicting Resistance to Nucleotide Excision Repair

Zhang

Geacintov

et al. 2018

Chem. Res. Toxicol.

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Nucleotide excision repair (NER) excises a variety of environmentally derived DNA lesions. However, NER efficiencies for structurally different DNA lesions can vary by orders of magnitude; yet the origin of this variance is poorly understood. Our goal is to develop computational strategies that predict and identify the most hazardous, repair-resistant lesions from the plethora of such adducts. In the present work, we are focusing on lesion recognition by the xeroderma pigmentosum C protein complex (XPC), the first and required step for the subsequent assembly of factors needed to produce successful NER. We have performed molecular dynamics simulations to characterize the initial binding of Rad4, the yeast orthologue of human XPC, to a library of 10 different lesion-containing DNA duplexes derived from environmental carcinogens. These vary in lesion chemical structures and conformations in duplex DNA and exhibit a wide range of relative NER efficiencies from repair resistant to highly susceptible. We have determined a promising set of structural descriptors that characterize initial binding of Rad4 to lesions that are resistant to NER. Key initial binding requirements for successful recognition are absent in the repair-resistant cases: There is little or no duplex unwinding, very limited interaction between the β-hairpin domain 2 of Rad4 and the minor groove of the lesion-containing duplex, and no conformational capture of a base on the lesion partner strand. By contrast, these key binding features are present to different degrees in NER susceptible lesions and correlate to their relative NER efficiencies. Furthermore, we have gained molecular understanding of Rad4 initial binding as determined by the lesion structures in duplex DNA and how the initial binding relates to the repair efficiencies. The development of a computational strategy for identifying NER-resistant lesions is grounded in this molecular understanding of the lesion recognition mechanism.

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“…Positive Pearson coefficients were found in several genes, including XAB2 metaphase delay 23 , UVRAG (pro autophagy and NOTCH positive regulator) 24 , and SFPQ, a multifunctional pro DNA repair gene 25 , which is also involved in the regulation of L1 retrotransposons and proliferation 26 . Two other genes in the DNA repair hallmark having positive Pearson coefficients include RAD23B (nucleotide excision repair) 27 , and ATXN3 (represses the tumor suppressor PTEN), which is associated with tumor proliferation in gastric, lung, and testicular cancers 28,29 .…”

Section: Predicted Gene Expression and Direct Effect Model Hazardmentioning

confidence: 99%

Measuring Cancer Hallmark Mediation of the TET1 Glioma Survival Effect with Linked Neural-Network Based Mediation Experiments

Luechtefeld¹,

Lin²,

Paller

et al. 2020

Sci Rep

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This paper examines the effect of TET1 expression on survival in glioma patients using open-access data from the Genomic Data Commons. A neural network-based survival model was built on expression data from a selection of genes most affected by TET1 knockdown with a median cross-validated survival concordance of 82.5%. A synthetic experiment was then conducted that linked two separately trained neural networks: a multitask model estimating cancer hallmark gene expression from TET1 expression, and a survival neural network. This experiment quantified the mediation of the TET1 survival effect through eight cancer hallmarks: apoptosis, cell cycle, cell death, cell motility, DNA repair, immune response, two phosphorylation pathways, and a randomized gene sets. Immune response, DNA repair, and apoptosis displayed greater mediation than the randomized gene set. Cell motility was inversely associated with only 12.5% mediated concordance. We propose the neural network linkage mediation experiment as an approach to collecting evidence of hazard mediation relationships with prognostic capacity useful for designing interventions. Gliomas represent approximately 75% of primary brain tumors in adults. The median survival of adult patients with gliomas is less than five years, with overall survival of 8-14 months for patients with glioblastoma multiforme (GBM) 1. The current standard of care includes surgery followed by radiation therapy and treatment with temozolomide. The therapy causes cells to die as a result of extensive DNA damage. Factors that contribute to recurrence are glioma invasiveness, the growth of cell populations resistant to radiation and temozolomide, and the blood brain barrier 2,3. Classifications of gliomas have been adding molecular features to histology for better diagnosis, especially under circumstances when histological phenotype is unclear. For example, the revised World Health Organization classifications now include 1p/19q co-deletion as a defining feature of oligodendroglial tumors 4. The use of molecular features will result in more precise prognosis and in the design of treatments tailored to the tumor. Resistance to the alkylating agent temozolomide is associated with promoter methylation of the gene encoding the DNA repair protein O6-methylguanine-DNA methyltransferase 5. We recently reported that glioma cell lines deficient with Tet methylcytosine dioxygenase 1 (TET1) exhibited greater genomic instability and were more resistant to ionizing radiation therapy 6. TET1 belongs to a family of enzymes comprised of three members that catalyzes the conversion of 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine (5-hmC), which is the initial step of DNA demethylation 7. We found that TET1-deficient cells displayed an attenuated DNA damage response (DDR). TET1-deficient cells fail to undergo apoptosis in response to ionizing radiation and have attenuated DNA repair resulting in high numbers of DNA strand breaks in the survival cell population 6,8. There has also been evidence indicating the involvem...

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Molecular basis for damage recognition and verification by XPC-RAD23B and TFIIH in nucleotide excision repair

Cited by 61 publications

References 115 publications

Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair

Ubiquitin and TFIIH-stimulated DDB2 dissociation drives DNA damage handover in nucleotide excision repair

Lesion Sensing during Initial Binding by Yeast XPC/Rad4: Toward Predicting Resistance to Nucleotide Excision Repair

Measuring Cancer Hallmark Mediation of the TET1 Glioma Survival Effect with Linked Neural-Network Based Mediation Experiments

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