Actual state of knowledge in the field of diseases related with defective nucleotide excision repair

Bukowska, Bożena; Karwowski, Bolesław T.

doi:10.1016/j.lfs.2017.12.035

Cited by 28 publications

(17 citation statements)

References 130 publications

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“…XPA is a protein that plays an essential role in both TC and GG NER. Patients with reported mutations in the XPA gene experience some of the most severe phenotypes of a disease called xeroderma pigmentosum (XP) and are at a significantly increased risk for skin cancer 5 . The exact function of XPA in NER remains controversial, as evidence exists for multiple roles.…”

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confidence: 99%

Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search

et al. 2020

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Nucleotide excision repair (NER) removes a wide range of DNA lesions, including UVinduced photoproducts and bulky base adducts. XPA is an essential protein in eukaryotic NER, although reports about its stoichiometry and role in damage recognition are controversial. Here, by PeakForce Tapping atomic force microscopy, we show that human XPA binds and bends DNA by ∼60°as a monomer. Furthermore, we observe XPA specificity for the helix-distorting base adduct N-(2'-deoxyguanosin-8-yl)-2-acetylaminofluorene over nondamaged dsDNA. Moreover, single molecule fluorescence microscopy reveals that DNAbound XPA exhibits multiple modes of linear diffusion between paused phases. The presence of DNA damage increases the frequency of pausing. Truncated XPA, lacking the intrinsically disordered N-and C-termini, loses specificity for DNA lesions and shows less pausing on damaged DNA. Our data are consistent with a working model in which monomeric XPA bends DNA, displays episodic phases of linear diffusion along DNA, and pauses in response to DNA damage.

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confidence: 99%

Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search

et al. 2020

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“…Xeroderma pigmentosum (XP) is a rare autosomal recessive disorder that is genetically heterogeneous due to seven complementation groups with defective NER and a variant group (XP-V) with normal NER [9]. Xeroderma pigmentosum complementation group E (XP-E) is one of the least common groups of XP.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel DDB2 mutation in a Chinese Han family with Xeroderma pigmentosum group E:a case report and literature review

et al. 2020

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Background: Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis. There are eight complementation groups of XP (XP-A to G and a variant form). XP-E is one of the least common forms, and XP-E patients are generally not diagnosed until they are adults due to a later onset of skin alterations. Case presentation: We report a case of a 28-year-old Chinese woman with freckle-like hyperpigmented macules in a sun-exposed area who is prone to develop basal cell carcinomas. A genetic study revealed a novel homozygous c.111_112del deletion in exon 1 of the DDB2 gene. Western blotting analysis revealed that the patient lacked the expression of the wild-type mature DDB2 protein. The proband was first diagnosed with XPE on the basis of clinical findings and genetic testing. Sun protection was recommended, and the patient did not develop any skin cancers during the one-year follow-up. Conclusions: We identified a novel homozygous deletion in DDB2 gene in Chinese XP-E patients having unique clinical features.

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“…Therefore, it is not surprising that cells require a well‐functioning DNA repair apparatus to be protected from endogenous and exogenous damaging agents and to preserve their healthy status. Likewise, defective DNA repair pathways are associated with rare genetic diseases, such as xeroderma pigmentosum, Cockayne's syndrome, and trichothiodystrophy, whose affected individuals show propensity for cancer, neurological deficiencies, and physical abnormalities (Bukowska & Karwowski, ; Cleaver, Lam, & Revet, ). Although DNA repair is essential to maintain genomic stability, these pathways can interfere with cancer therapies by repairing the damage inflicted on tumor cells, allowing cancer to progress.…”

Section: Introductionmentioning

confidence: 99%

Computer‐aided drug design of small molecule inhibitors of the ERCC1‐XPF protein–protein interaction

et al. 2020

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The heterodimer of DNA excision repair protein ERCC‐1 and DNA repair endonuclease XPF (ERCC1‐XPF) is a 5′–3′ structure‐specific endonuclease essential for the nucleotide excision repair (NER) pathway, and it is also involved in other DNA repair pathways. In cancer cells, ERCC1‐XPF plays a central role in repairing DNA damage induced by chemotherapeutics including platinum‐based and cross‐linking agents; thus, its inhibition is a promising strategy to enhance the effect of these therapies. In this study, we rationally modified the structure of F06, a small molecule inhibitor of the ERCC1‐XPF interaction (Molecular Pharmacology, 84, 2013 and 12), to improve its binding to the target. We followed a multi‐step computational approach to investigate potential modification sites of F06, rationally design and rank a library of analogues, and identify candidates for chemical synthesis and in vitro testing. Our top compound, B5, showed an improved half‐maximum inhibitory concentration (IC50) value of 0.49 µM for the inhibition of ERCC1‐XPF endonuclease activit, and lays the foundation for further testing and optimization. Also, the computational approach reported here can be used to develop DNA repair inhibitors targeting the ERCC1‐XPF complex.

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Actual state of knowledge in the field of diseases related with defective nucleotide excision repair

Cited by 28 publications

References 130 publications

Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search

Single molecule analysis reveals monomeric XPA bends DNA and undergoes episodic linear diffusion during damage search

Identification of a novel DDB2 mutation in a Chinese Han family with Xeroderma pigmentosum group E:a case report and literature review

Computer‐aided drug design of small molecule inhibitors of the ERCC1‐XPF protein–protein interaction

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