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. 2010 Dec 16:2010:592980.
doi: 10.4061/2010/592980.

Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair

Rajesh P Rastogi  1 , Richa, Ashok Kumar, Madhu B Tyagi, Rajeshwar P Sinha
Affiliations

Molecular mechanisms of ultraviolet radiation-induced DNA damage and repair

Rajesh P Rastogi et al. J Nucleic Acids. .

Abstract

DNA is one of the prime molecules, and its stability is of utmost importance for proper functioning and existence of all living systems. Genotoxic chemicals and radiations exert adverse effects on genome stability. Ultraviolet radiation (UVR) (mainly UV-B: 280-315 nm) is one of the powerful agents that can alter the normal state of life by inducing a variety of mutagenic and cytotoxic DNA lesions such as cyclobutane-pyrimidine dimers (CPDs), 6-4 photoproducts (6-4PPs), and their Dewar valence isomers as well as DNA strand breaks by interfering the genome integrity. To counteract these lesions, organisms have developed a number of highly conserved repair mechanisms such as photoreactivation, base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR). Additionally, double-strand break repair (by homologous recombination and nonhomologous end joining), SOS response, cell-cycle checkpoints, and programmed cell death (apoptosis) are also operative in various organisms with the expense of specific gene products. This review deals with UV-induced alterations in DNA and its maintenance by various repair mechanisms.

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Figures

Figure 1
Figure 1
DNA damage and maintenance. Genomic lesions produced by various DNA damaging agents trigger several specific repair machinery to conserve the genomic integrity. In case of severe damage and/or failure of repair mechanisms, cells undergo apoptosis or induce a complex series of phenotypic changes, that is, SOS response. Sometimes the potentiality of lesions in the genome is mitigated by a phenomenon known as damage tolerance, during which DNA lesions are recognized by certain repair machinery, allowing the cells to undergo normal replication and gene expression. The cellular response to DNA damage may activate cell-cycle checkpoint by means of a network of signaling pathway that gives the cell extra time to repair the genomic lesions or may induce cell suicide response/programmed cell death (PCD).
Figure 2
Figure 2
Structures of DNA duplexes showing the presence of lesions (in green) such as CPD (a), 6-4PP (b), and 6-4 Dewar dimer (c). Hydrogen atoms are not shown, prepared from PDB entries 1TTD [24], 1CFL [25], and 1QKG [26] using PyMol. (version 1.1r1) [27].
Figure 3
Figure 3
Pathway of UVR-induced T-T (a) and T-C (b) CPD, 6-4PPs, and their Dewar isomers.
Figure 4
Figure 4
Possible diastereoisomers of pyrimidine T <> T dimer.
Figure 5
Figure 5
Formation of cytosine photohydrate (6-hydroxy-5,6-dihydrocytosine) as a result of photohydration reaction.
Figure 6
Figure 6
Structure of purinic photoproduct, that is, adenine dimer, porschke photoproduct and thymine-adenine photoadduct.
Figure 7
Figure 7
Cis-syn CPD showing the right-handed or left-handed twist in DNA duplex. Dotted arrows elucidate the strongest nuclear overhauser enhancement (NOE) interaction in both cases (Adopted from Lukin and de los Santos [75]).
Figure 8
Figure 8
Schematic representation showing different pathways of DSBs.
Figure 9
Figure 9
Photoreactivation: incidence of ultraviolet radiation (UVR) results in pyrimidine lesion (thymine dimer), which is recognized by a photoreactivating enzyme “photolyase”. The light energy (>380 nm) is trapped by the antenna molecules of photolyase (such as MTHF/8-HDF/FMN) and transfers them to catalytic cofactor FADH− which becomes excited and transfers energy to the pyrimidine dimer in the form of e−, splitting the CPD into two monomeric unit, and then electron is transferred back to the flavin molecule.
Figure 10
Figure 10
Schematic overview of mammalian SP-BER (a), and LP-BER (b). SP-BER is initiated by the activity of glycosylase and APE1, followed by scaffold protein XRCC1 and pol. β to remove the damaged nucleotide and DNA ligase III seals the nick. In case of LP-BER, after DNA damage by ionizing radiation, PNK is recruited to convert the damaged ends to 3′OH and 5′P moieties. Here PARP1/2, followed by XRCC1, is involved. PCNA and DNA pol. β and/or pol. −δ/ε extend and fill the gap by >2 nucleotides. Replication factor-C (RFC) is required to load the PCNA on DNA. Ultimately the resulting 5′flap of DNA is removed by the flap endonuclease I (FEN1) and subsequently the nick is sealed by DNA ligase I.
Figure 11
Figure 11
Molecular mechanisms of global genome nucleotide excision repair (GG-NER) and transcriptional coupled nucleotide excision repair (TC-NER) in mammals. For details see the text.
Figure 12
Figure 12
Different pathway for recognition of DNA lesions such as CPD and 6-4PP. In case of CPD photoproduct (cause little distortion), XPC complex binds to the lesion after recruitment of UV-DDB whereas 6-4PP that distorts the DNA helix to a great extent can be recognized either by interacting with prebound UV-DDB or directly by XPC complex.
Figure 13
Figure 13
Schematic representation of recombinational repair by (a) non-homologous end joining (NHEJ), and (b) homologous recombination (HR).
Figure 14
Figure 14
SOS response: As a result of massive DNA damage and failure of all possible repair mechanisms, RecA proteins is expressed, which activate the auto breakdown of LexA proteins, allowing the induction of all SOS responding genes. The pathway of SOS response is reversed when damages are repaired through the damage specific mechanisms. Here the inactivation of RecA protein allows the accumulation of LexA, which bind to SOS promoters and repress all SOS responding genes. SOS response is highly mutagenic due to involvement of DNA polymerase V/IV.
Figure 15
Figure 15
Schematic illustration of DNA damage-induced cell-cycle checkpoint activation (for details, see text).
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