scholarly journals The Effect of DNA Replication Mutations on CAG Tract Stability in Yeast

Genetics ◽  
1999 ◽  
Vol 152 (3) ◽  
pp. 953-963 ◽  
Author(s):  
Jill Kuglin Schweitzer ◽  
Dennis M Livingston
Keyword(s):  
Dna Replication ◽  
Proliferating Cell Nuclear Antigen ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Nuclear Antigen ◽  
Temperature Sensitive ◽  
Simple Repeats ◽  
Proliferating Cell ◽  
Lagging Strand ◽  
Palindromic Sequences

AbstractCAG repeat tracts are unstable in yeast, leading to frequent contractions and infrequent expansions in repeat tract length. To compare CAG repeats to other simple repeats and palindromic sequences, we examined the effect of DNA replication mutations, including alleles of pol α, pol δ, pol ϵ, and PCNA (proliferating cell nuclear antigen), on tract stability. Among the polymerase mutations, the pol δ mutation (pol3-14) destabilizes tracts with either CAG or CTG as the lagging strand template. One pol α mutation, pol1-1, destabilizes the orientation with CAG as the lagging strand template, but it has little effect on the CTG orientation. In contrast, the pol1-17 mutation has no effect on either orientation. Similarly, mutations in the proofreading functions of pol δ and pol ϵ, as well as a temperature-sensitive pol ϵ mutation, pol2-18, have no effect on tract stability. Three PCNA mutations, pol30-52, pol30-79, and pol30-90, all have drastic effects on tract stability. Of the three, pol30-52 is unique in yielding small tract changes that are indicative of an impairment in mismatch repair. These results show that while CAG repeats are destabilized by many of the same mutations that destabilize other simple repeats, they also have some behaviors that are suggestive of their potential to form hairpin structures.

scholarly journals Fission Yeast Cdc24 Is a Replication Factor C- and Proliferating Cell Nuclear Antigen-Interacting Factor Essential for S-Phase Completion

1999 ◽  
Vol 19 (2) ◽  
pp. 1038-1048 ◽  
Author(s):  
Hiroyuki Tanaka ◽  
Koichi Tanaka ◽  
Hiroshi Murakami ◽  
Hiroto Okayama
Keyword(s):  
Dna Replication ◽  
Fission Yeast ◽  
Proliferating Cell Nuclear Antigen ◽  
Large Subunit ◽  
Nuclear Antigen ◽  
Temperature Sensitive ◽  
Replication Factor C ◽  
Replication Factor ◽  
Factor C ◽  
Proliferating Cell

ABSTRACT At the nonpermissive temperature the fission yeastcdc24-M38 mutant arrests in the cell cycle with incomplete DNA replication as indicated by pulsed-field gel electrophoresis. Thecdc24 + gene encodes a 501-amino-acid protein with no significant homology to any known proteins. The temperature-sensitive cdc24 mutant is effectively rescued by pcn1 +, rfc1 + (a fission yeast homologue of RFC1), andhhp1 +, which encode the proliferating cell nuclear antigen (PCNA), the large subunit of replication factor C (RFC), and a casein kinase I involved in DNA damage repair, respectively. The Cdc24 protein binds PCNA and RFC1 in vivo, and the domains essential for Cdc24 function and for RFC1 and PCNA binding colocalize in the N-terminal two-thirds of the molecule. In addition,cdc24 + genetically interacts with the gene encoding the catalytic subunit of DNA polymerase ɛ, which is stimulated by PCNA and RFC, and with those encoding the fission yeast counterparts of Mcm2, Mcm4, and Mcm10. These results indicate that Cdc24 is an RFC- and PCNA-interacting factor required for DNA replication and might serve as a target for regulation.

scholarly journals Maneuvers on PCNA Rings during DNA Replication and Repair

Genes ◽  
2018 ◽  
Vol 9 (8) ◽  
pp. 416 ◽  
Author(s):  
Dea Slade
Keyword(s):  
Dna Replication ◽  
Protein Interactions ◽  
Proliferating Cell Nuclear Antigen ◽  
Binding Proteins ◽  
Nuclear Antigen ◽  
Vast Number ◽  
Post Translational Modifications ◽  
Dna Replication And Repair ◽  
Replicative Polymerases ◽  
Proliferating Cell

DNA replication and repair are essential cellular processes that ensure genome duplication and safeguard the genome from deleterious mutations. Both processes utilize an abundance of enzymatic functions that need to be tightly regulated to ensure dynamic exchange of DNA replication and repair factors. Proliferating cell nuclear antigen (PCNA) is the major coordinator of faithful and processive replication and DNA repair at replication forks. Post-translational modifications of PCNA, ubiquitination and acetylation in particular, regulate the dynamics of PCNA-protein interactions. Proliferating cell nuclear antigen (PCNA) monoubiquitination elicits ‘polymerase switching’, whereby stalled replicative polymerase is replaced with a specialized polymerase, while PCNA acetylation may reduce the processivity of replicative polymerases to promote homologous recombination-dependent repair. While regulatory functions of PCNA ubiquitination and acetylation have been well established, the regulation of PCNA-binding proteins remains underexplored. Considering the vast number of PCNA-binding proteins, many of which have similar PCNA binding affinities, the question arises as to the regulation of the strength and sequence of their binding to PCNA. Here I provide an overview of post-translational modifications on both PCNA and PCNA-interacting proteins and discuss their relevance for the regulation of the dynamic processes of DNA replication and repair.

Fibroblast proliferation during myocardial development in rats is regulated by IGF-1 receptors

1995 ◽  
Vol 269 (3) ◽  
pp. H943-H951 ◽  
Author(s):  
K. Reiss ◽  
W. Cheng ◽  
J. Kajstura ◽  
E. H. Sonnenblick ◽  
L. G. Meggs ◽  
...  
Keyword(s):  
Dna Replication ◽  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Cardiac Fibroblasts ◽  
Nuclear Antigen ◽  
Dna Polymerase Alpha ◽  
Myocardial Development ◽  
Left And Right ◽  
Proliferating Cell

To determine whether the growth of cardiac fibroblasts during development is modulated by the insulin-like growth factor (IGF)-1 receptor (IGF-1R), the expression of IGF-1, IGF-2, and IGF-1R was determined in fibroblasts from fetal and postnatal hearts. The expression of proliferating cell nuclear antigen (PCNA) and DNA polymerase-alpha was also evaluated in combination with the estimation of DNA replication. In comparison with fetal hearts, at postnatal day 21, fibroblast expression of IGF-1R mRNA, IGF-2, PCNA, and DNA polymerase-alpha was reduced by 77, 70, 80, and 86%, respectively. Moreover, IGF-1R protein decreased by 48% at 21 days. Bromodeoxyuridine labeling decreased by 88 and 89% in the left and right ventricle, respectively, at this time. Two different antisense oligodeoxynucleotides to IGF-1R reduced DNA replication by 60 and 44% in fibroblasts in culture. In addition, this intervention markedly attenuated the growth response of fibroblasts to IGF-1 or serum. In conclusion, the IGF-1R system appears to play a major role in the regulation of fibroblast growth in the heart in vivo.

scholarly journals K6-linked SUMOylation of BAF regulates nuclear integrity and DNA replication in mammalian cells

2020 ◽  
Vol 117 (19) ◽  
pp. 10378-10387 ◽  
Author(s):  
Qiaoyu Lin ◽  
Bin Yu ◽  
Xiangyang Wang ◽  
Shicong Zhu ◽  
Gan Zhao ◽  
...  
Keyword(s):  
Dna Replication ◽  
Nuclear Localization ◽  
Proliferating Cell Nuclear Antigen ◽  
Mammalian Cells ◽  
Regulatory Mechanism ◽  
Nuclear Antigen ◽  
Multiple Functions ◽  
And Function ◽  
Proliferating Cell ◽  
Replication Failure

Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.

scholarly journals Structure of the processive human Pol δ holoenzyme

2019 ◽  
Author(s):  
Claudia Lancey ◽  
Muhammad Tehseen ◽  
Vlad-Stefan Raducanu ◽  
Fahad Rashid ◽  
Nekane Merino ◽  
...  
Keyword(s):  
Dna Polymerase ◽  
Proliferating Cell Nuclear Antigen ◽  
Nuclear Antigen ◽  
Structural Basis ◽  
Catalytic Core ◽  
Regulatory Subunits ◽  
Functional Interactions ◽  
Proliferating Cell ◽  
Lagging Strand ◽  
Catalytic Cleft

In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ-DNA-PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ’s activity in replicating the human genome.

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