Short CCG repeat in huntingtin gene is an obstacle for replicative DNA polymerases, potentially hampering progression of replication fork

Hang Phuong Le, Yuji Masuda, Toshiki Tsurimoto, Satoko Maki, Tsutomu Katayama, Asako Furukohri, Hisaji Maki

研究成果: ジャーナルへの寄稿記事

2 引用 (Scopus)

抄録

Trinucleotide repeats (TNRs) are highly unstable in genomes, and their expansions are linked to human disorders. DNA replication is reported to be involved in TNR instability, but the current models are insufficient in explaining TNR expansion is induced during replication. Here, we investigated replication fork progression across huntingtin (HTT)-gene-derived fragments using an Escherichia coli oriC plasmid DNA replication system. We found most of the forks to travel smoothly across the HTT fragments even when the fragments had a pathological length of CAG/CTG repeats (approximately 120 repeats). A little fork stalling in the fragments was observed, but it occurred within a short 3'-flanking region downstream of the repeats. This region contains another short TNR, (CCG/CGG)7, and the sense strand containing CCG repeats appeared to impede the replicative DNA polymerase Pol III. Examining the behavior of the human leading and lagging replicative polymerases Pol epsilon (hPolε) and Pol delta (hPolδ) on this sequence, we found hPolδ replicating DNA across the CCG repeats but hPolε stalling at the CCG repeats even if the secondary structure is eliminated by a single-stranded binding protein. These findings offer insights into the distinct behavior of leading and lagging polymerases at CCG/CGG repeats, which may be important for understanding the process of replication arrest and genome instability at the HTT gene.

元の言語英語
ページ(範囲)817-833
ページ数17
ジャーナルGenes to Cells
20
発行部数10
DOI
出版物ステータス出版済み - 10 1 2015

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Trinucleotide Repeats
DNA-Directed DNA Polymerase
DNA Polymerase III
DNA Replication
Trinucleotide Repeat Expansion
3' Flanking Region
Genes
Genomic Instability
Carrier Proteins
Plasmids
Genome
Escherichia coli
DNA

All Science Journal Classification (ASJC) codes

  • Genetics
  • Cell Biology

これを引用

Short CCG repeat in huntingtin gene is an obstacle for replicative DNA polymerases, potentially hampering progression of replication fork. / Le, Hang Phuong; Masuda, Yuji; Tsurimoto, Toshiki; Maki, Satoko; Katayama, Tsutomu; Furukohri, Asako; Maki, Hisaji.

:: Genes to Cells, 巻 20, 番号 10, 01.10.2015, p. 817-833.

研究成果: ジャーナルへの寄稿記事

Le, Hang Phuong ; Masuda, Yuji ; Tsurimoto, Toshiki ; Maki, Satoko ; Katayama, Tsutomu ; Furukohri, Asako ; Maki, Hisaji. / Short CCG repeat in huntingtin gene is an obstacle for replicative DNA polymerases, potentially hampering progression of replication fork. :: Genes to Cells. 2015 ; 巻 20, 番号 10. pp. 817-833.
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abstract = "Trinucleotide repeats (TNRs) are highly unstable in genomes, and their expansions are linked to human disorders. DNA replication is reported to be involved in TNR instability, but the current models are insufficient in explaining TNR expansion is induced during replication. Here, we investigated replication fork progression across huntingtin (HTT)-gene-derived fragments using an Escherichia coli oriC plasmid DNA replication system. We found most of the forks to travel smoothly across the HTT fragments even when the fragments had a pathological length of CAG/CTG repeats (approximately 120 repeats). A little fork stalling in the fragments was observed, but it occurred within a short 3'-flanking region downstream of the repeats. This region contains another short TNR, (CCG/CGG)7, and the sense strand containing CCG repeats appeared to impede the replicative DNA polymerase Pol III. Examining the behavior of the human leading and lagging replicative polymerases Pol epsilon (hPolε) and Pol delta (hPolδ) on this sequence, we found hPolδ replicating DNA across the CCG repeats but hPolε stalling at the CCG repeats even if the secondary structure is eliminated by a single-stranded binding protein. These findings offer insights into the distinct behavior of leading and lagging polymerases at CCG/CGG repeats, which may be important for understanding the process of replication arrest and genome instability at the HTT gene.",
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