Some features of base pair mismatch repair and its role in the formation of genetic recombinants

For the formation of recombinants involving closely linked markers, two distinct processes play a role. The recombinational interaction between homologous DNA molecules results in the presence of heteroduplex DNA joining the parental components of the recombinant. The presence of markers distinguishing the parents in the region of heteroduplex DNA can result in base pair mismatches. The post recombination repair of such mismatches can contribute to the separation of closely linked markers. The processes responsible for such repair also play roles in mutation avoidance. The specificities, functions and contribution to the formation of recombinants for closely linked markers of the processes inEscherichia coli are described.     

Mismatch repair as an important source of new mutations in non-dividing cells

This paper describes a mechanism which permits somatic cells to generate random mutations in the complete absence of cell proliferation. Knowledge of the existence of this mechanism should provide us with the basis for a better understanding of a number of important biological phenomena, and in particular may help to explain the origins of many human cancers.     

Human MutY: gene structure,protein functions and interactions,and role in carcinogenesis

Faithful maintenance of the genome is crucial to the individual and the species. Oxidative DNA damage, such as 8-oxo-7,8-dihydroguanine (8-oxoG), poses a major threat to genomic integrity. 8-OxoG can mispair with 2-deoxycytidine 5-triphosphate or with 2-deoxyadenosine triphosphate during DNA replication, forming C8-oxoG and A8-oxoG mispairs. Human MutY is responsible for recognition and removal of the inappropriately inserted adenine in an A8-oxoG mispair. If unrepaired, the A8-oxoG mispairs can result in deleterious C:G to A:T transversions. Human MutY functions in a postreplication repair pathway and is targeted to the newly synthesized daughter strand of DNA for removal of the adenine base. The human MutY protein is targeted to both the mitochondria and the nucleus and associates with the proliferating cell nuclear antigen, apurinic/ apyrimidinic endonuclease 1, replication protein A and mutS homolog 6 proteins. Mutations in the human MutY gene and defective activity of the human MutY protein have been detected in cancer. A direct correlation between defective A8-oxoG repair and increased levels of genomic 8-oxoG has now been established.Received 10 February 2003; received after revision 7 April 2003; accepted 14 April 2003     

Gene conversion in the chicken immunoglobulin locus: A paradigm of homologous recombination in higher eukaryotes

Gene conversion was first defined in yeast as a type of homologous recombination in which the donor sequence does not change. In chicken B cells, gene conversion builds the antigen receptor repertoire by introducing sequence diversity into the immunoglobulin genes. Immunoglobulin gene conversion continues at high frequency in an avian leukosis virus induced chicken B cell line. This cell line can be modified by homologous integration of transfected DNA constructs offering a model system for studying gene conversion in higher eukaryotes. In search for genes which might participate in chicken immunoglobulin gene conversion, we have identified chicken counterparts of the yeastRAD51, RAD52, andRAD54 genes. Disruption and overexpression of these genes in the chicken B cell line may clarify their role in gene conversion and gene targeting.     

Participation of DNA repair in the response to 5-fluorouracil

The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer. Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated. Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of DNA repair in order to improve the efficacy of current anticancer treatments. Received 08 September 2008; received after revision 25 September 2008; accepted 03 October 2008     

Histone methylation and ubiquitination with their cross-talk and roles in gene expression and stability

Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore, is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation and roles in controlling gene expression and stability. Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008     

Current topics in genome evolution: Molecular mechanisms of new gene formation

Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species. These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition events. Received 18 October 2006; received after revision 18 November 2006; accepted 28 November 2006     

Aspects of gene polymorphisms in cerebral infarction: inflammatory cytokines

During the last decade, a growing corpus of evidence has indicated an important role of inflammatory cytokines in the pathogenesis of cerebral lesion following stroke. Recent data suggest that genetics may in turn contribute to modulating the effects of inflammatory cytokines on cerebral infarction (CI). This paper reviews the physiologic characteristics of major inflammatory cytokines and recent research developments related to cell biology and pathobiology in CI. In particular, this review focuses on the genetic aspects of inflammatory cytokines and their implications in CI.Received 22 June 2004; received after revision 11 November 2004; accepted 16 December 2004