Human DNA Repair Genes

Image

Human DNA Repair Genes

Introduction

Cellular DNA is subjected to continual attack, both by reactive species inside cells and by environmental agents. Toxic and mutagenic consequences are minimized by distinct pathways of repair, and 130 known human DNA repair genes are described here. Notable features presently include four enzymes that can remove uracil from DNA, seven recombination genes related to RAD51, and many recently discovered DNA polymerases that bypass damage, but only one system to remove the main DNA lesions induced by ultraviolet light. More human DNA repair genes will be found by comparison with model organisms and as common folds in three-dimensional protein structures are determined. Modulation of DNA repair should lead to clinical applications including improvement of radiotherapy and treatment with anticancer drugs and an advanced understanding of the cellular aging process.

 

Basic mechanism of repair

DNA single-strand interruptions that cannot be directly rejoined by a DNA ligase are common lesions generated by reactive oxygen species. They are often corrected by a short-patch excision-repair process related to the later steps in BER. The mammalian polynucleotide kinase phosphatase (PNKP) can serve a useful initial role in such single-strand break repair, since this 57 kDa enzyme possesses both an activity for phosphorylation of DNA termini with a 5′-OH group, and an activity for dephosphorylation at 3′-termini. These activities are the same as those of the commonly used reagent PNK of phage T4 origin. RNA-mediated down-regulation of human PNKP in tissue culture experiments [8] induces hypersensitivity to several DNA-damaging agents, delayed repair of γ-radiation induced single-strand breaks, and a seven-fold higher spontaneous mutation frequency, strongly indicating a direct role of human PNKP in DNA repair. Further, the NEIL1 and NEIL2 DNA glycosylases have associated AP lyase activities that can generate strand breaks with 3′ phosphate termini at damaged sites. PNKP is then required for processing of these blocked DNA termini.

 

One unusual form of DNA strand break can result from interruption of topoisomerase I-induced relaxation of a super coiled DNA structure. If the intermediate is trapped as a cleavage complex, which could be a consequence of damage to either DNA or the protein, or enzyme inhibition, the topoisomerase remains covalently attached by a 3′-phosphotyrosine residue. A specific Tyr-DNA phosphodiesterase (TDP1) hydrolyzes the bond linking tyrosine to a 3′ DNA end. This enzyme was first discovered in yeast, and the human counterpart and its gene have been defined. TDP1 associates with the BER enzyme DNA ligase III, which provides further evidence for a role in correction of certain types of DNA single-strand interruptions. The neurodegenerative disease spinocerebellar ataxia with axonal neuropathy (SCAN1) is caused by mutations in the human TDP1 gene. SCAN1-deficient individuals have defective single-strand break repair, although they do not appear to exhibit chromosome instability or increased cancer frequency.

 

Direct reversal of DNA damage

Single-stranded regions of DNA at transcription bubbles and replication forks are particularly susceptible to damage by alkylating agents, such as methyl methanesulphonate (MMS). The major lesions introduced are the cytotoxic bases 1-methyladenine and 3-methylcytosine, generated by alkylation at sites that are protected in double-stranded DNA. These lesions were recently found to be processed by an unanticipated strategy of DNA repair, oxidative demethylation with release of the methyl group as formaldehyde. The first example of this mode of repair was the E. coli AlkB protein, and two human functional counterparts, ABH2 and ABH3, were then described. These nuclear DNA dioxygenases employ Fe2+ and α-ketoglutarate as cofactors and directly revert DNA damage by a free-radical mechanism. The two human enzymes also act on the minor alkylation lesion 3-methylthymine, which differs from 3-methylcytosine and 1-methyladenine by being uncharged at neutral pH.

 

Nucleotide excision repair (NER)

An additional entry regarding the NER pathway is the gene for a recently recognized 10th subunit of TFIIH. Both yeast and mammalian TFIIH have such a subunit, designated Tfb5 in S. cerevisiae and TFB5 or TTDA in human cells. The TTDA/GTF2H5 gene encodes a small protein of ∼8 kDa that was overlooked for some time in TFIIH preparation. This subunit is not absolutely required for transcription or NER, but cells defective in TTDA have lower than normal amounts of TFIIH, because TTDA functions to stabilize the TFIIH complex. Mutations in the gene occur in complementation group A of the sunlight-sensitive inherited disorder trichothiodystrophy. A eukaryotic Tfb5 ortholog was first identified in the alga Chlamydomonas reinhardtii and designated REX1. Mutants in this algal gene are defective in the removal of UV radiation-induced cyclobutane pyrimidine dimers from DNA.

Our Journal is planning to release a year end special issue has announced almost 50% discount on article publication charges to celebrate its journey for publishing articles with in the short time.

The Journal will publish original articles, reviews, technical notes, editorials, news and views (commentaries, science policy issues, ethical and legal issues, patient organizations, industry needs and alliances, regulatory issues, etc.), and letters to the editor.

The Journal invites different types of articles including original research article, review articles, short note communications, case reports, Editorials, letters to the Editors and expert opinions & commentaries from different regions for publication.

 The Journals includes around 150Abstracts and 100 Keynote speakers have given their valuable words. The meet has provided a great scope for interaction of professionals including in addition to clinical experts and top-level pathologists and scientists from around the globe, on a single platform.
 

Media Contact:
ALPINE
Managing Editor

Journal of Molecular Oncology Research
Email: oncology@openaccessjournal.org