Coordinated processing of 3′ slipped (CAG)n/(CTG) n hairpins by DNA polymerases β and δ preferentially induces repeat expansions

Nelson L.S. Chan, Jinzhen Guo, Tianyi Zhang, Guogen Mao, Caixia Hou, Fenghua Yuan, Jian Huang, Yanbin Zhang, Jianxin Wu, Liya Gu, Guo Min Li

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Expansion of CAG/CTG trinucleotide repeats causes certain familial neurological disorders. Hairpin formation in the nascent strand during DNA synthesis is considered a major path for CAG/CTG repeat expansion. However, the underlying mechanism is unclear. We show here that removal or retention of a nascent strand hairpin during DNA synthesis depends on hairpin structures and types of DNA polymerases. Polymerase (pol) δ alone removes the 3′-slipped hairpin using its 3′-5′ proofreading activity when the hairpin contains no immediate 3′ complementary sequences. However, in the presence of pol β, pol δ preferentially facilitates hairpin retention regardless of hairpin structures. In this reaction, pol β incorporates several nucleotides to the hairpin 3′-end, which serves as an effective primer for the continuous DNA synthesis by pol δ, thereby leading to hairpin retention and repeat expansion. These findings strongly suggest that coordinated processing of 3′-slipped (CAG) n/(CTG)n hairpins by polymerases δ and β on during DNA synthesis induces CAG/CTG repeat expansions.

Original languageEnglish (US)
Pages (from-to)15015-15022
Number of pages8
JournalJournal of Biological Chemistry
Volume288
Issue number21
DOIs
StatePublished - May 24 2013

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DNA-Directed DNA Polymerase
DNA
Processing
Trinucleotide Repeats
Nervous System Diseases
Nucleotides

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Coordinated processing of 3′ slipped (CAG)n/(CTG) n hairpins by DNA polymerases β and δ preferentially induces repeat expansions. / Chan, Nelson L.S.; Guo, Jinzhen; Zhang, Tianyi; Mao, Guogen; Hou, Caixia; Yuan, Fenghua; Huang, Jian; Zhang, Yanbin; Wu, Jianxin; Gu, Liya; Li, Guo Min.

In: Journal of Biological Chemistry, Vol. 288, No. 21, 24.05.2013, p. 15015-15022.

Research output: Contribution to journalArticle

Chan, Nelson L.S. ; Guo, Jinzhen ; Zhang, Tianyi ; Mao, Guogen ; Hou, Caixia ; Yuan, Fenghua ; Huang, Jian ; Zhang, Yanbin ; Wu, Jianxin ; Gu, Liya ; Li, Guo Min. / Coordinated processing of 3′ slipped (CAG)n/(CTG) n hairpins by DNA polymerases β and δ preferentially induces repeat expansions. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 21. pp. 15015-15022.
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abstract = "Expansion of CAG/CTG trinucleotide repeats causes certain familial neurological disorders. Hairpin formation in the nascent strand during DNA synthesis is considered a major path for CAG/CTG repeat expansion. However, the underlying mechanism is unclear. We show here that removal or retention of a nascent strand hairpin during DNA synthesis depends on hairpin structures and types of DNA polymerases. Polymerase (pol) δ alone removes the 3′-slipped hairpin using its 3′-5′ proofreading activity when the hairpin contains no immediate 3′ complementary sequences. However, in the presence of pol β, pol δ preferentially facilitates hairpin retention regardless of hairpin structures. In this reaction, pol β incorporates several nucleotides to the hairpin 3′-end, which serves as an effective primer for the continuous DNA synthesis by pol δ, thereby leading to hairpin retention and repeat expansion. These findings strongly suggest that coordinated processing of 3′-slipped (CAG) n/(CTG)n hairpins by polymerases δ and β on during DNA synthesis induces CAG/CTG repeat expansions.",
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AU - Mao, Guogen

AU - Hou, Caixia

AU - Yuan, Fenghua

AU - Huang, Jian

AU - Zhang, Yanbin

AU - Wu, Jianxin

AU - Gu, Liya

AU - Li, Guo Min

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N2 - Expansion of CAG/CTG trinucleotide repeats causes certain familial neurological disorders. Hairpin formation in the nascent strand during DNA synthesis is considered a major path for CAG/CTG repeat expansion. However, the underlying mechanism is unclear. We show here that removal or retention of a nascent strand hairpin during DNA synthesis depends on hairpin structures and types of DNA polymerases. Polymerase (pol) δ alone removes the 3′-slipped hairpin using its 3′-5′ proofreading activity when the hairpin contains no immediate 3′ complementary sequences. However, in the presence of pol β, pol δ preferentially facilitates hairpin retention regardless of hairpin structures. In this reaction, pol β incorporates several nucleotides to the hairpin 3′-end, which serves as an effective primer for the continuous DNA synthesis by pol δ, thereby leading to hairpin retention and repeat expansion. These findings strongly suggest that coordinated processing of 3′-slipped (CAG) n/(CTG)n hairpins by polymerases δ and β on during DNA synthesis induces CAG/CTG repeat expansions.

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