Skin Cancer: Lights on Genome Lesions

Lima-Bessa, Keronninn M.; Menck, Carlos Frederico Martins

doi:10.1016/j.cub.2004.12.056

Cited by 28 publications

(18 citation statements)

References 18 publications

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“…These studies therefore suggest that (6 -4)PP lesions are more potent on the induction of apoptosis than CPD lesions, which tend to induce cell cycle arrest. These results corroborate the hypothesis that in NER-deficient cells both lesions have equally important roles on outcome after UV radiation but that on DNA repair-proficient cells only CPDs are responsible for the induction of apoptosis, probably due to the rapid repair of (6 -4)PP by NER [98].…”

Section: Photolyase In Mammalssupporting

confidence: 88%

DNA Repair in Mammalian Cells

Eker

Quayle

Chaves

et al. 2009

Cell. Mol. Life Sci.

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The genomic integrity of all living organisms is constantly jeopardized by physical [e.g. ultraviolet (UV) light, ionizing radiation] and chemical (e.g. environmental pollutants, endogenously produced reactive metabolites) agents that damage the DNA. To overcome the deleterious effects of DNA lesions, nature evolved a number of complex multi-protein repair processes with broad, partially overlapping substrate specificity. In marked contrast, cells may use very simple repair systems, referred to as direct DNA damage reversal, that rely on a single protein, remove lesions in a basically error-free manner, show high substrate specificity, and do not involve incision of the sugar-phosphate backbone or base excision. This concise review deals with two types of direct DNA damage reversal: (i) the repair of alkylating damage by alkyltransferases and dioxygenases, and (ii) the repair of UV-induced damage by spore photoproduct lyases and photolyases. (Part of a Multi-author Review).

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Section: Photolyase In Mammalssupporting

confidence: 88%

DNA Repair in Mammalian Cells

Eker

Quayle

Chaves

et al. 2009

Cell. Mol. Life Sci.

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“…DNA repair photocycle | ultrafast enzyme dynamics | thymine dimer splitting | electron tunneling pathway | active-site mutation U ltraviolet (UV) component of sunlight irradiation causes DNA damage by inducing the formation of cyclobutane pyrimidine dimer (CPD), which is mutagenic and a leading cause of skin cancer (1)(2)(3). CPD can be completely restored by a photoenzyme, photolyase, through absorption of visible blue light (4).…”

mentioning

confidence: 99%

Dynamics and mechanism of cyclobutane pyrimidine dimer repair by DNA photolyase

Liu

Tan

Guo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

152

250

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Photolyase uses blue light to restore the major ultraviolet (UV)-induced DNA damage, the cyclobutane pyrimidine dimer (CPD), to two normal bases by splitting the cyclobutane ring. Our earlier studies showed that the overall repair is completed in 700 ps through a cyclic electron-transfer radical mechanism. However, the two fundamental processes, electron-tunneling pathways and cyclobutane ring splitting, were not resolved. Here, we use ultrafast UV absorption spectroscopy to show that the CPD splits in two sequential steps within 90 ps and the electron tunnels between the cofactor and substrate through a remarkable route with an intervening adenine. Site-directed mutagenesis reveals that the active-site residues are critical to achieving high repair efficiency, a unique electrostatic environment to optimize the redox potentials and local flexibility, and thus balance all catalytic reactions to maximize enzyme activity. These key findings reveal the complete spatio-temporal molecular picture of CPD repair by photolyase and elucidate the underlying molecular mechanism of the enzyme's high repair efficiency.DNA repair photocycle | ultrafast enzyme dynamics | thymine dimer splitting | electron tunneling pathway | active-site mutation U ltraviolet (UV) component of sunlight irradiation causes DNA damage by inducing the formation of cyclobutane pyrimidine dimer (CPD), which is mutagenic and a leading cause of skin cancer (1-3). CPD can be completely restored by a photoenzyme, photolyase, through absorption of visible blue light (4). In our early work (5-7), we have observed a cyclic electron-transfer (ET) reaction in thymine dimer (ThiT) repair by photolyase and determined the time scale of 700 ps for the complete repair photocycle (7). However, the central questions of whether the splitting of the cyclobutane ring is synchronously or asynchronously concerted or stepwise and whether the cyclic ET involves specific tunneling pathways were not resolved. Furthermore, the molecular mechanism underlying the high repair efficiency has not been elucidated. Here, using femtosecond spectroscopy and site-directed mutagenesis, we are able to measure the dynamics of all initial reactants, reaction intermediates, and final products with different substrates and with wild-type and active-site mutant enzymes, and thus reveal the complete spatio-temporal molecular picture of thymine dimer repair by photolyase.Photolyase contains a fully reduced flavin adenine dinucleotide (FADH − ) as the catalytic cofactor and electron donor (4). Based on previous studies (4-10), a sequential repair mechanism of thymine dimer splitting is shown in Fig. 1. Previously, we found that the forward ET from FADH − Ã to ThiT occurs in 250 ps (1∕k FET ) and the total decay of intermediate FADH• in 700 ps (1∕k total ) (5, 7). These dynamics usually follow a stretched-exponential decay behavior, reflecting heterogeneous ET dynamics controlled by the active-site solvation (5, 6, 11). However, in that study, no thymine-related species could be detected in the vi...

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“…21 In mammalian cells, these lesions in genomic DNA are repaired by nucleotide excision repair (NER) pathway. After lesion recognition, the excision step in NER process causes a single-stranded DNA gap, which requires 24-32 deoxynucleotides incorporation in each gap to complete the repair.…”

Section: Resultsmentioning

confidence: 99%

The contribution of CMP kinase to the efficiency of DNA repair

et al. 2015

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Abbreviations: dNTP, deoxynucleoside triphosphates; CMPK, CMP/UMP kinase; RNR, ribonucleotide reductase; 6-4 pp, photoproduct; R1C, C-terminal fragment of R1 subunit of RNR.Cellular supply of deoxynucleoside triphosphates (dNTPs) is crucial for DNA replication and repair. In this study, we investigated the role of CMP/UMP kinase (CMPK), an enzyme catalyzes CDP formation, in DNA repair. Knockdown of CMPK delays DNA repair during recovery from UV damage in serum-deprived cells but not in the cells without serum deprivation. Exogenous supply of cytidine or deoxycytidine facilitates DNA repair dependent on CMPK in serumdeprived cells, suggesting that the synthesis of dCDP or CDP determines the rate of repair. However, CMPK knockdown does not affect the steady state level of dCTP in serum-deprived cells. We then found the localization of CMPK at DNA damage sites and its complex formation with Tip60 and ribonucleotide reductase. Our analysis demonstrated that the N-terminal 32-amino-acid of CMPK is required for its recruitment to DNA damage sites in a Tip60-dependent manner. Re-expression of wild-type but not N-terminus deleted CMPK restores the efficiency of DNA repair in CMPK knockdown cells. We proposed that site-specific dCDP formation via CMPK provides a means to facilitate DNA repair in serumdeprived cells.

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Skin Cancer: Lights on Genome Lesions

Abstract: Sunlight generates skin damage mainly by inducing DNA lesions in epidermal cells. The recent development of transgenic mice expressing specific photolyases has identified cyclobutane pyrimidine dimers as the major player in ultraviolet-induced damage, including skin cancer.

Cited by 28 publications

References 18 publications

DNA Repair in Mammalian Cells

DNA Repair in Mammalian Cells

Dynamics and mechanism of cyclobutane pyrimidine dimer repair by DNA photolyase

The contribution of CMP kinase to the efficiency of DNA repair

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