Biomedical subjects

Christophe Kunz

Publications and source records attributed to Christophe Kunz.

5 recordsLinked to original sources

PubMed2006

The enigmatic thymine DNA glycosylase.

When it was first isolated from extracts of HeLa cells in Josef Jiricny's laboratory, the thymine DNA glycosylase (TDG) attracted attention because of its ability to remove thymine, i.e. a normal DNA base, from G.T mispairs. This implicated a function of DNA base excision repair in the restoration of G.C base pairs following the deamination of a 5-methylcytosine. TDG turned out to be the founding member of a newly emerging family of mismatch-directed uracil-DNA glycosylases, the MUG proteins, that act on a comparably broad spectrum of base lesion including G.U as the common, most efficiently processed substrate. However, because of its apparent catalytic inefficiency, some have considered TDG a poor DNA repair enzyme without an important biological function. Others have reported 5-meC DNA glycosylase activity to be associated with TDG, thrusting the enzyme into limelight as a possible DNA demethylase. Yet others have found the glycosylase to interact with transcription factors, implicating a function in gene regulation, which appears to be critically important in developmental processes. This article reviews all these developments in view of possible biological functions of this multifaceted DNA glycosylase.

Amino Acid Sequence↗

PubMed2004

Meiotic recombination: sealing the partnership at the junction.

Crossovers ensure proper chromosome segregation in meiosis. A heterodimer of MutS proteins, hMSH4-hMSH5, has recently been found to interact with recombination intermediates in a manner that suggests a mechanism for directing meiotic DNA double strand break repair towards a crossover pathway.

Adenosine Triphosphatases↗

PubMed2003

Mutagenesis of the HMGB (high-mobility group B) protein Cmb1 (cytosine-mismatch binding 1) of Schizosaccharomyces pombe: effects on recognition of DNA mismatches and damage.

Cmb1 (cytosine-mismatch binding 1) is a high-mobility group (HMG) protein of Schizosaccharomyces pombe, which consists of 223 amino acids and has a single HMG domain at the C-terminal end. We have created several mutant and deletion forms of the Cmb1 protein and studied the effects on general DNA binding and specific binding to DNA mismatches and damaged DNA. Cmb1Delta41 (i.e. Cmb1 from which the 41 N-terminal amino acids have been deleted) bound specifically to cytosine-containing mismatches, to the cisplatin-induced intrastrand cross-links cis -GG and cis -AG and to an O (6)-methylguanine lesion. DNA binding was not affected when the 45 N-terminal amino acids were deleted, but was abolished in the absence of the 50 N-terminal amino acids, and was reduced when Cmb1 was truncated by between five and eleven C-terminal amino acids. Cmb1, both with and without the C-terminal truncations, retained its DNA binding affinity after heating at 95 degrees C. The cmb1 gene was induced when S. pombe cells were treated with cisplatin. Mitotic mutation rates were increased in a S. pombe cmb1 null mutant and in a cmb1-(1-212) mutant, which encodes a Cmb1 protein lacking the 11 C-terminal amino acids. We conclude that mutation avoidance by Cmb1 is distinct from Msh2-dependent mismatch repair, but related to nucleotide excision repair.

Antineoplastic Agents↗

PubMed2003

Repair of damaged and mismatched DNA by the XPC homologues Rhp41 and Rhp42 of fission yeast.

Rhp41 and Rhp42 of Schizosaccharomyces pombe are homologues of human XPC, which is involved in nucleotide excision repair (NER) of damaged DNA. Inactivation of rhp41 caused moderate sensitivity to ultraviolet (UV) radiation. In addition, an increase of mitotic mutation rates was observed in the rhp41 mutant, which was dependent on active translesion polymerase Z. UV sensitivity and mutation rates were not different between rhp42 and wild type, but compared to rhp41 were further increased in rhp41 rhp42 cells. Transcription of the fbp1 gene (induced in vegetative cells) and of the SPBC1289.14 gene (induced during meiosis) was strongly blocked by UV-induced damages in the rhp41 mutant, but not, or only slightly, reduced in rhp42 background. NER-dependent short-patch repair of mismatches formed during meiosis was slightly affected in rhp41, moderately affected in rhp42, and absent in rhp41 rhp42. Epistasis analysis with rhp7 and rhp26 indicates that Rhp41 and Rhp42 are both involved in the global genome and transcription-coupled repair subpathways of NER. Rhp41 plays a major role in damage repair and Rhp42 in mismatch repair.

Alleles↗

PubMed2002

DNA mismatch repair and mutation avoidance pathways.

Unpaired and mispaired bases in DNA can arise by replication errors, spontaneous or induced base modifications, and during recombination. The major pathway for correction of mismatches arising during replication is the MutHLS pathway of Escherichia coli and related pathways in other organisms. MutS initiates repair by binding to the mismatch, and activates together with MutL the MutH endonuclease, which incises at hemimethylated dam sites and thereby mediates strand discrimination. Multiple MutS and MutL homologues exist in eukaryotes, which play different roles in the mismatch repair (MMR) pathway or in recombination. No MutH homologues have been identified in eukaryotes, suggesting that strand discrimination is different to E. coli. Repair can be initiated by the heterodimers MSH2-MSH6 (MutSalpha) and MSH2-MSH3 (MutSbeta). Interestingly, MSH3 (and thus MutSbeta) is missing in some genomes, as for example in Drosophila, or is present as in Schizosaccharomyces pombe but appears to play no role in MMR. MLH1-PMS1 (MutLalpha) is the major MutL homologous heterodimer. Again some, but not all, eukaryotes have additional MutL homologues, which all form a heterodimer with MLH1 and which play a minor role in MMR. Additional factors with a possible function in eukaryotic MMR are PCNA, EXO1, and the DNA polymerases delta and epsilon. MMR-independent pathways or factors that can process some types of mismatches in DNA are nucleotide-excision repair (NER), some base excision repair (BER) glycosylases, and the flap endonuclease FEN-1. A pathway has been identified in Saccharomyces cerevisiae and human that corrects loops with about 16 to several hundreds of unpaired nucleotides. Such large loops cannot be processed by MMR.

Adenosine Triphosphatases↗