NDLI: Coordination between Polymerase β and FEN1 Can Modulate CAG Repeat Expansion*

Content Provider	PubMed Central
Author	Liu, Yuan Prasad, Rajendra Beard, William A. Hou, Esther W. Horton, Julie K. Mcmurray, Cynthia T. Wilson, Samuel H.
Abstract	The oxidized DNA base 8-oxoguanine (8-oxoG) is implicated in neuronal CAG repeat expansion associated with Huntington disease, yet it is unclear how such a DNA base lesion and its repair might cause the expansion. Here, we discovered size-limited expansion of CAG repeats during repair of 8-oxoG in a wild-type mouse cell extract. This expansion was deficient in extracts from cells lacking pol β and HMGB1. We demonstrate that expansion is mediated through pol β multinucleotide gap-filling DNA synthesis during long-patch base excision repair. Unexpectedly, FEN1 promotes expansion by facilitating ligation of hairpins formed by strand slippage. This alternate role of FEN1 and the polymerase β (pol β) multinucleotide gap-filling synthesis is the result of uncoupling of the usual coordination between pol β and FEN1. HMGB1 probably promotes expansion by stimulating APE1 and FEN1 in forming single strand breaks and ligatable nicks, respectively. This is the first report illustrating that disruption of pol β and FEN1 coordination during long-patch BER results in CAG repeat expansion.
Related Links	http://dx.doi.org/10.1074/jbc.m109.050286
Ending Page	28366
Page Count	15
Starting Page	28352
File Format	PDF
ISSN	00219258
e-ISSN	1083351X
Journal	The Journal of Biological Chemistry
Issue Number	41
Volume Number	284
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2009-10-09
Access Restriction	Open
Rights Holder	American Society for Biochemistry and Molecular Biology
Subject Keyword	Cell Biology Biochemistry Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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