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Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein


Clement, F C; Camenisch, U; Fei, J; Kaczmarek, N; Mathieu, N; Naegeli, H (2010). Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein. Mutation Research, 685(1-2):21-28.

Abstract

The recognition and subsequent repair of DNA damage are essential reactions for the maintenance of genome stability. A key general sensor of DNA lesions is xeroderma pigmentosum group C (XPC) protein, which recognizes a wide variety of helix-distorting DNA adducts arising from ultraviolet (UV) radiation, genotoxic chemicals and reactive metabolic byproducts. By detecting damaged DNA sites, this unique molecular sensor initiates the global genome repair (GGR) pathway, which allows for the removal of all the aforementioned lesions by a limited repertoire of excision factors. A faulty GGR activity causes the accumulation of DNA adducts leading to mutagenesis, carcinogenesis, neurological degeneration and other traits of premature aging. Recent findings indicate that XPC protein achieves its extraordinary substrate versatility by an entirely indirect readout strategy implemented in two clearly discernible stages. First, the XPC subunit uses a dynamic sensor interface to monitor the double helix for the presence of non-hydrogen-bonded bases. This initial screening generates a transient nucleoprotein intermediate that subsequently matures into the ultimate recognition complex by trapping undamaged nucleotides in the abnormally oscillating native strand, in a way that no direct contacts are made between XPC protein and the offending lesion itself. It remains to be elucidated how accessory factors like Rad23B, centrin-2 or the UV-damaged DNA-binding complex contribute to this dynamic two-stage quality control process.

The recognition and subsequent repair of DNA damage are essential reactions for the maintenance of genome stability. A key general sensor of DNA lesions is xeroderma pigmentosum group C (XPC) protein, which recognizes a wide variety of helix-distorting DNA adducts arising from ultraviolet (UV) radiation, genotoxic chemicals and reactive metabolic byproducts. By detecting damaged DNA sites, this unique molecular sensor initiates the global genome repair (GGR) pathway, which allows for the removal of all the aforementioned lesions by a limited repertoire of excision factors. A faulty GGR activity causes the accumulation of DNA adducts leading to mutagenesis, carcinogenesis, neurological degeneration and other traits of premature aging. Recent findings indicate that XPC protein achieves its extraordinary substrate versatility by an entirely indirect readout strategy implemented in two clearly discernible stages. First, the XPC subunit uses a dynamic sensor interface to monitor the double helix for the presence of non-hydrogen-bonded bases. This initial screening generates a transient nucleoprotein intermediate that subsequently matures into the ultimate recognition complex by trapping undamaged nucleotides in the abnormally oscillating native strand, in a way that no direct contacts are made between XPC protein and the offending lesion itself. It remains to be elucidated how accessory factors like Rad23B, centrin-2 or the UV-damaged DNA-binding complex contribute to this dynamic two-stage quality control process.

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Additional indexing

Item Type:Journal Article, refereed, further contribution
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pharmacology and Toxicology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2010
Deposited On:09 Nov 2010 13:27
Last Modified:05 Apr 2016 14:15
Publisher:Elsevier
ISSN:0027-5107
Funders:others
Publisher DOI:10.1016/j.mrfmmm.2009.08.005
PubMed ID:19686765
Permanent URL: http://doi.org/10.5167/uzh-35827

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