Expansions of CAG Repeat Tracts are Frequent in a Yeast Mutant Defective in Okazaki Fragment Maturation

Schweitzer, Jill Kuglin; Livingston, Dennis

doi:10.1093/hmg/7.1.69

Cited by 169 publications

(132 citation statements)

References 36 publications

Supporting

Mentioning

115

Contrasting

Order By: Relevance

“…Bacterial and yeast models of TNR instability tend to delete repeat tracts, with only rare instances of expansion 19,21,22,24 . In these systems, deletions predominate regardless of the direction of replication; however, the frequency of deletions is greater when the CTG strand is the template for lagging-strand synthesis 19,21,22,24 . Unlike bacterial and yeast models 19,21,22 , the effect of replication direction in our primate system manifested as differences in mutation type (expansions versus deletions).…”

Section: Effect Of Replication Directionmentioning

confidence: 99%

“…Longer rather than shorter nascent repeat tracts at Okazaki termini might form these structures more readily. The metabolism of the structural intermediates may lead to efficient or error-prone processing by replication 22,24,[32][33][34] , repair 37,46,47 or recombination proteins [43][44][45]48 , all of which could lead to instability. Although other explanations are possible, it is clear that striking differences in (CTG)•(CAG) stability result from the location of replication initiation relative to the repeat tract.…”

Section: Replication Fork Dynamics and Dynamic Mutationsmentioning

confidence: 99%

“…Bacterial (Escherichia coli) 19,20 and yeast (Saccharomyces cerevisiae) [21][22][23][24] models support a role for DNA replication in TNR instability in that the direction of replication through the TNR tract affects its stability. In bacterial and yeast systems, repeat deletions predominate regardless of the direction of replication, but the frequency of deletions is higher when the CTG strand, rather than the CAG strand, is the template for lagging-strand synthesis 19 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells

Cleary

Nichol

Wang³

et al. 2002

Nat Genet

179

192

View full text Add to dashboard Cite

show abstract

Section: Effect Of Replication Directionmentioning

confidence: 99%

Section: Replication Fork Dynamics and Dynamic Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells

Cleary

Nichol

Wang³

et al. 2002

Nat Genet

179

192

View full text Add to dashboard Cite

show abstract

“…Consistent with its crucial role in DNA replication and repair, FEN1 is highly expressed in all proliferative tissues, and its activity is key for the maintenance of genomic integrity (5). FEN1 has been identified as a cancer susceptibility gene, and mutations in it have been linked to a number of genetic diseases, such as EM map myotonic dystrophy, Huntington disease, several ataxias, fragile X syndrome, and cancer (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

Querol-Audí

Cheng

et al. 2012

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

View full text Add to dashboard Cite

Processivity clamps such as proliferating cell nuclear antigen (PCNA) and the checkpoint sliding clamp Rad9/Rad1/Hus1 (9-1-1) act as versatile scaffolds in the coordinated recruitment of proteins involved in DNA replication, cell-cycle control, and DNA repair. Association and handoff of DNA-editing enzymes, such as flap endonuclease 1 (FEN1), with sliding clamps are key processes in biology, which are incompletely understood from a mechanistic point of view. We have used an integrative computational and experimental approach to define the assemblies of FEN1 with double-flap DNA substrates and either proliferating cell nuclear antigen or the checkpoint sliding clamp 9-1-1. Fully atomistic models of these two ternary complexes were developed and refined through extensive molecular dynamics simulations to expose their conformational dynamics. Clustering analysis revealed the most dominant conformations accessible to the complexes. The cluster centroids were subsequently used in conjunction with single-particle electron microscopy data to obtain a 3D EM reconstruction of the human 9-1-1/FEN1/DNA assembly at 18-Å resolution. Comparing the structures of the complexes revealed key differences in the orientation and interactions of FEN1 and double-flap DNA with the two clamps that are consistent with their respective functions in providing inherent flexibility for lagging strand DNA replication or inherent stability for DNA repair.F lap endonuclease 1 (FEN1) belongs to a class of essential nucleases (the FEN1 5′ nuclease superfamily) present in all domains of life (1). FEN1 catalyzes the endonucleolytic cleavage of bifurcated DNA or RNA structures known as 5′ flaps. These 5′ flaps are generated during lagging strand DNA synthesis or during long-patch base excision repair. The FEN1 substrates are in fact double-flap DNA (dfDNA) with DNA on the opposite side of the 5′ flap, forming a single nucleotide 3′ flap when bound to the enzyme (2, 3). By removing the 5′ ssDNA or RNA flap from such substrates, FEN1 produces a single nicked product that could be sealed by the subsequent action of a DNA ligase (4). Consistent with its crucial role in DNA replication and repair, FEN1 is highly expressed in all proliferative tissues, and its activity is key for the maintenance of genomic integrity (5). FEN1 has been identified as a cancer susceptibility gene, and mutations in it have been linked to a number of genetic diseases, such as EM map myotonic dystrophy, Huntington disease, several ataxias, fragile X syndrome, and cancer (6-10).The nuclease activity of FEN1 can be stimulated by association with processivity clamps such as proliferating cell nuclear antigen (PCNA), which encircle DNA at sites of replication and repair (11)(12)(13). PCNA is a recognized master coordinator of cellular responses to DNA damage and interacts with numerous DNA repair and cell-cycle control proteins. In this capacity, PCNA serves not only as a mobile platform for the attachment of these proteins to DNA but, importantly, plays an active role in the recru...

show abstract

“…Recently, a haploinsufficiency of fen-1 in mice was shown to lead to rapid tumor progression, where tumors from mice showed microsatellite instability (Kucherlapati et al 2002). Thus, Fen-1 protein in humans is assumed to reduce the induction of genetic diseases characterized by a trinucleotide repeat expansion, such as myotic dystrophy, Huntington's disease, and fragile X syndrome (Schweitzer and Livingston 1998;White et al 1999). Based on the duplication/addition mutator phenotype, Nagata et al (2002) hypothesized that sequence expansion would occur in the nascent DNA during lagging-strand synthesis, forming a mismatch bulge, and PolI would bind and recognize this bulge in the nascent DNA during Okazaki fragment processing to remove the mismatch structure using the 5' 3' exonuclease.…”

mentioning

confidence: 99%

Saccharomyces cerevisiae RAD27 complements its Escherichia coli homolog in damage repair but not mutation avoidance

et al. 2004

View full text Add to dashboard Cite

In eukaryotes, the flap endonuclease of Rad27/Fen-1 is thought to play a critical role in lagging-strand DNA replication by removing ribonucleotides present at the 5' ends of Okazaki fragments, and in base excision repair by cleaving a 5' flap structure that may result during base excision repair. Saccharomyces cerevisiae rad27 D mutants further display a repeat tract instability phenotype and a high rate of forward mutations to canavanine resistance that result from duplications of DNA sequence, indicating a role in mutation avoidance. Two conserved motifs in Rad27/Fen-1 show homology to the 5' 3' exonuclease domain of Escherichia coli DNA polymerase I. The strain defective in the 5' 3' exonuclease domain in DNA polymerase I shows essentially the same phenotype as the yeast rad27 D strain. In this study, we expressed the yeast RAD27 gene in an E. coli strain lacking the 5' 3' exonuclease domain in DNA polymerase I in order to test whether eukaryotic RAD27/FEN-1 can complement the defect of its bacterial homolog. We found that the yeast Rad27 protein complements sensitivity to methyl methanesulfonate in an E. coli mutant. On the other hand, Rad27 protein did not reduce the high rate of spontaneous mutagenesis in the E. coli tonB gene which results from duplication of DNA. These results indicate that the yeast Rad27 and E. coli 5' 3' exonuclease act on the same substrate. We argue that the lack of mutation avoidance of yeast RAD27 in E. coli results from a lack of interaction between the yeast Rad27 protein and the E. coli replication clamp ( bclamp).

show abstract

Expansions of CAG Repeat Tracts are Frequent in a Yeast Mutant Defective in Okazaki Fragment Maturation

Cited by 169 publications

References 36 publications

Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells

Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells

Repair complexes of FEN1 endonuclease, DNA, and Rad9-Hus1-Rad1 are distinguished from their PCNA counterparts by functionally important stability

Saccharomyces cerevisiae RAD27 complements its Escherichia coli homolog in damage repair but not mutation avoidance

Contact Info

Product

Resources

About