Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats

Craig Spiro; Richard Pelletier; Michael L. Rolfsmeier; Michael J. Dixon; Robert S. Lahue; Goutam Gupta; Min S. Park; Xian Chen; S. V.Santhana Mariappan; Cynthia T. McMurray

doi:10.1016/S1097-2765(00)80236-1

Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats

Craig Spiro
, Richard Pelletier
, Michael L. Rolfsmeier
, Michael J. Dixon
, Robert S. Lahue
, Goutam Gupta
, Min S. Park
, Xian Chen
, S. V.Santhana Mariappan
, Cynthia T. McMurray

Department of Pharmacology
University of Nebraska Medical Center
Los Alamos National Laboratory
Mayo Clinic Graduate School of Biomedical Sciences
Mayo Clinic

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

161 Citations (Scopus)

Abstract

The mechanism by which trinucleotide expansion occurs in human genes is not understood. However, it has been hypothesized that DNA secondary structure may actively participate by preventing FEN-1 cleavage of displaced Okazaki fragments. We show here that secondary structure can, indeed, play a role in expansion by a FEN-1-dependent mechanism. Secondary structure inhibits flap processing at CAG, CGG, or CTG repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by FEN-1. Thus, secondary structure can defeat the protective function of FEN-1, leading to site-specific expansions. However, when FEN-1 is absent from the cell, alternative pathways to simple inhibition of flap processing contribute to expansion.

Original language	English
Pages (from-to)	1079-1085
Number of pages	7
Journal	Molecular Cell
Volume	4
Issue number	6
DOIs	https://doi.org/10.1016/S1097-2765(00)80236-1
Publication status	Published - Dec 1999
Externally published	Yes

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10.1016/S1097-2765(00)80236-1

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title = "Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats",

abstract = "The mechanism by which trinucleotide expansion occurs in human genes is not understood. However, it has been hypothesized that DNA secondary structure may actively participate by preventing FEN-1 cleavage of displaced Okazaki fragments. We show here that secondary structure can, indeed, play a role in expansion by a FEN-1-dependent mechanism. Secondary structure inhibits flap processing at CAG, CGG, or CTG repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by FEN-1. Thus, secondary structure can defeat the protective function of FEN-1, leading to site-specific expansions. However, when FEN-1 is absent from the cell, alternative pathways to simple inhibition of flap processing contribute to expansion.",

author = "Craig Spiro and Richard Pelletier and Rolfsmeier, \{Michael L.\} and Dixon, \{Michael J.\} and Lahue, \{Robert S.\} and Goutam Gupta and Park, \{Min S.\} and Xian Chen and Mariappan, \{S. V.Santhana\} and McMurray, \{Cynthia T.\}",

year = "1999",

month = dec,

doi = "10.1016/S1097-2765(00)80236-1",

language = "English",

volume = "4",

pages = "1079--1085",

journal = "Molecular Cell",

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TY - JOUR

T1 - Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats

AU - Spiro, Craig

AU - Pelletier, Richard

AU - Rolfsmeier, Michael L.

AU - Dixon, Michael J.

AU - Lahue, Robert S.

AU - Gupta, Goutam

AU - Park, Min S.

AU - Chen, Xian

AU - Mariappan, S. V.Santhana

AU - McMurray, Cynthia T.

PY - 1999/12

Y1 - 1999/12

N2 - The mechanism by which trinucleotide expansion occurs in human genes is not understood. However, it has been hypothesized that DNA secondary structure may actively participate by preventing FEN-1 cleavage of displaced Okazaki fragments. We show here that secondary structure can, indeed, play a role in expansion by a FEN-1-dependent mechanism. Secondary structure inhibits flap processing at CAG, CGG, or CTG repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by FEN-1. Thus, secondary structure can defeat the protective function of FEN-1, leading to site-specific expansions. However, when FEN-1 is absent from the cell, alternative pathways to simple inhibition of flap processing contribute to expansion.

AB - The mechanism by which trinucleotide expansion occurs in human genes is not understood. However, it has been hypothesized that DNA secondary structure may actively participate by preventing FEN-1 cleavage of displaced Okazaki fragments. We show here that secondary structure can, indeed, play a role in expansion by a FEN-1-dependent mechanism. Secondary structure inhibits flap processing at CAG, CGG, or CTG repeats in a length-dependent manner by concealing the 5' end of the flap that is necessary for both binding and cleavage by FEN-1. Thus, secondary structure can defeat the protective function of FEN-1, leading to site-specific expansions. However, when FEN-1 is absent from the cell, alternative pathways to simple inhibition of flap processing contribute to expansion.

UR - https://www.scopus.com/pages/publications/0033369989

U2 - 10.1016/S1097-2765(00)80236-1

DO - 10.1016/S1097-2765(00)80236-1

M3 - Article

C2 - 10635332

AN - SCOPUS:0033369989

SN - 1097-2765

VL - 4

SP - 1079

EP - 1085

JO - Molecular Cell

JF - Molecular Cell

IS - 6

ER -

Inhibition of FEN-1 processing by DNA secondary structure at trinucleotide repeats

Abstract

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