AP endonuclease-independent DNA base excision repair in human cells

Lee Wiederhold; John B. Leppard; Padmini Kedar; Feridoun Karimi-Busheri; Aghdass Rasouli-Nia; Michael Weinfeld; Alan E. Tomkinson; Tadahide Izumi; Rajendra Prasad; Samuel H. Wilson; Sankar Mitra; Tapas K. Hazra

doi:10.1016/j.molcel.2004.06.003

AP endonuclease-independent DNA base excision repair in human cells

Lee Wiederhold, John B. Leppard, Padmini Kedar, Feridoun Karimi-Busheri, Aghdass Rasouli-Nia, Michael Weinfeld, Alan E. Tomkinson, Tadahide Izumi, Rajendra Prasad, Samuel H. Wilson, Sankar Mitra, Tapas K. Hazra

Research output: Contribution to journal › Article › peer-review

415 Scopus citations

Abstract

The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3′ blocking groups (including 3′ phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3′ phosphate termini. Here we show that in mammalian cells, removal of the 3′ phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase β (pol β) and DNA ligase IIIα. The complex of NEIL1, pol β, and DNA ligase IIIα together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals.

Original language	English
Pages (from-to)	209-220
Number of pages	12
Journal	Molecular Cell
Volume	15
Issue number	2
DOIs	https://doi.org/10.1016/j.molcel.2004.06.003
State	Published - Jul 23 2004

Bibliographical note

Funding Information:
This research was supported by USPHS grants CA92584 (S.M. and A.E.T.), CA81063, CA53791, and ES06676 (S.M.), and GM47251 and GM57479 (A.E.T.), Training Grant T32-07254 (A.E.T.), and Canadian Institutes of Health Research grant MOP-15385 (M.W.). We thank Rabindra Roy for supplying human NTH1, Keith W. Caldecott for the DNA ligase IIIα expression plasmid, Michael P. Thelen for anti-XRCC1 antibody, and Kosuke Akiyama for the APE2 cDNA clone. We thank David Konkel for editing and Bruce Demple, Ella Englander, R.S. Lloyd, and Priscilla Cooper for critically reviewing the manuscript.

Funding

This research was supported by USPHS grants CA92584 (S.M. and A.E.T.), CA81063, CA53791, and ES06676 (S.M.), and GM47251 and GM57479 (A.E.T.), Training Grant T32-07254 (A.E.T.), and Canadian Institutes of Health Research grant MOP-15385 (M.W.). We thank Rabindra Roy for supplying human NTH1, Keith W. Caldecott for the DNA ligase IIIα expression plasmid, Michael P. Thelen for anti-XRCC1 antibody, and Kosuke Akiyama for the APE2 cDNA clone. We thank David Konkel for editing and Bruce Demple, Ella Englander, R.S. Lloyd, and Priscilla Cooper for critically reviewing the manuscript.

Funders	Funder number
National Institute of General Medical Sciences	R29GM047251
U.S. Public Health Service	T32-07254, GM57479, CA53791, ES06676, CA92584, CA81063
Canadian Institutes of Health Research	MOP-15385

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/j.molcel.2004.06.003

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title = "AP endonuclease-independent DNA base excision repair in human cells",

abstract = "The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3′ blocking groups (including 3′ phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3′ phosphate termini. Here we show that in mammalian cells, removal of the 3′ phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase β (pol β) and DNA ligase IIIα. The complex of NEIL1, pol β, and DNA ligase IIIα together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals.",

author = "Lee Wiederhold and Leppard, {John B.} and Padmini Kedar and Feridoun Karimi-Busheri and Aghdass Rasouli-Nia and Michael Weinfeld and Tomkinson, {Alan E.} and Tadahide Izumi and Rajendra Prasad and Wilson, {Samuel H.} and Sankar Mitra and Hazra, {Tapas K.}",

note = "Funding Information: This research was supported by USPHS grants CA92584 (S.M. and A.E.T.), CA81063, CA53791, and ES06676 (S.M.), and GM47251 and GM57479 (A.E.T.), Training Grant T32-07254 (A.E.T.), and Canadian Institutes of Health Research grant MOP-15385 (M.W.). We thank Rabindra Roy for supplying human NTH1, Keith W. Caldecott for the DNA ligase IIIα expression plasmid, Michael P. Thelen for anti-XRCC1 antibody, and Kosuke Akiyama for the APE2 cDNA clone. We thank David Konkel for editing and Bruce Demple, Ella Englander, R.S. Lloyd, and Priscilla Cooper for critically reviewing the manuscript.",

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T1 - AP endonuclease-independent DNA base excision repair in human cells

AU - Wiederhold, Lee

AU - Leppard, John B.

AU - Kedar, Padmini

AU - Karimi-Busheri, Feridoun

AU - Rasouli-Nia, Aghdass

AU - Weinfeld, Michael

AU - Tomkinson, Alan E.

AU - Izumi, Tadahide

AU - Prasad, Rajendra

AU - Wilson, Samuel H.

AU - Mitra, Sankar

AU - Hazra, Tapas K.

N1 - Funding Information: This research was supported by USPHS grants CA92584 (S.M. and A.E.T.), CA81063, CA53791, and ES06676 (S.M.), and GM47251 and GM57479 (A.E.T.), Training Grant T32-07254 (A.E.T.), and Canadian Institutes of Health Research grant MOP-15385 (M.W.). We thank Rabindra Roy for supplying human NTH1, Keith W. Caldecott for the DNA ligase IIIα expression plasmid, Michael P. Thelen for anti-XRCC1 antibody, and Kosuke Akiyama for the APE2 cDNA clone. We thank David Konkel for editing and Bruce Demple, Ella Englander, R.S. Lloyd, and Priscilla Cooper for critically reviewing the manuscript.

PY - 2004/7/23

Y1 - 2004/7/23

N2 - The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3′ blocking groups (including 3′ phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3′ phosphate termini. Here we show that in mammalian cells, removal of the 3′ phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase β (pol β) and DNA ligase IIIα. The complex of NEIL1, pol β, and DNA ligase IIIα together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals.

AB - The paradigm for repair of oxidized base lesions in genomes via the base excision repair (BER) pathway is based on studies in Escherichia coli, in which AP endonuclease (APE) removes all 3′ blocking groups (including 3′ phosphate) generated by DNA glycosylase/AP lyases after base excision. The recently discovered mammalian DNA glycosylase/AP lyases, NEIL1 and NEIL2, unlike the previously characterized OGG1 and NTH1, generate DNA strand breaks with 3′ phosphate termini. Here we show that in mammalian cells, removal of the 3′ phosphate is dependent on polynucleotide kinase (PNK), and not APE. NEIL1 stably interacts with other BER proteins, DNA polymerase β (pol β) and DNA ligase IIIα. The complex of NEIL1, pol β, and DNA ligase IIIα together with PNK suggests coordination of NEIL1-initiated repair. That NEIL1/PNK could also repair the products of other DNA glycosylases suggests a broad role for this APE-independent BER pathway in mammals.

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JF - Molecular Cell

IS - 2

ER -

AP endonuclease-independent DNA base excision repair in human cells

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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