Lamin A/C promotes DNA base excision repair

Scott Maynard; Guido Keijzers; Mansour Akbari; Michael Ben Ezra; Arnaldur Hall; Marya Morevati; Morten Scheibye-Knudsen; Susana Gonzalo; Jiri Bartek; Vilhelm A Bohr

doi:10.1093/nar/gkz912

Lamin A/C promotes DNA base excision repair

Scott Maynard, Guido Keijzers, Mansour Akbari, Michael Ben Ezra, Arnaldur Hall, Marya Morevati, Morten Scheibye-Knudsen, Susana Gonzalo, Jiri Bartek, Vilhelm A Bohr

10 Citations (Scopus)

Abstract

The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.

Original language	English
Journal	Nucleic Acids Research
ISSN	0305-1048
DOIs	https://doi.org/10.1093/nar/gkz912
Publication status	Published - 16 Dec 2019

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title = "Lamin A/C promotes DNA base excision repair",

abstract = "The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.",

author = "Scott Maynard and Guido Keijzers and Mansour Akbari and Ezra, {Michael Ben} and Arnaldur Hall and Marya Morevati and Morten Scheibye-Knudsen and Susana Gonzalo and Jiri Bartek and Bohr, {Vilhelm A}",

note = "Published by Oxford University Press on behalf of Nucleic Acids Research 2019.",

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doi = "10.1093/nar/gkz912",

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T1 - Lamin A/C promotes DNA base excision repair

AU - Maynard, Scott

AU - Keijzers, Guido

AU - Akbari, Mansour

AU - Ezra, Michael Ben

AU - Hall, Arnaldur

AU - Morevati, Marya

AU - Scheibye-Knudsen, Morten

AU - Gonzalo, Susana

AU - Bartek, Jiri

AU - Bohr, Vilhelm A

N1 - Published by Oxford University Press on behalf of Nucleic Acids Research 2019.

PY - 2019/12/16

Y1 - 2019/12/16

N2 - The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.

AB - The A-type lamins (lamin A/C), encoded by the LMNA gene, are important structural components of the nuclear lamina. LMNA mutations lead to degenerative disorders known as laminopathies, including the premature aging disease Hutchinson-Gilford progeria syndrome. In addition, altered lamin A/C expression is found in various cancers. Reports indicate that lamin A/C plays a role in DNA double strand break repair, but a role in DNA base excision repair (BER) has not been described. We provide evidence for reduced BER efficiency in lamin A/C-depleted cells (Lmna null MEFs and lamin A/C-knockdown U2OS). The mechanism involves impairment of the APE1 and POLβ BER activities, partly effectuated by associated reduction in poly-ADP-ribose chain formation. Also, Lmna null MEFs displayed reduced expression of several core BER enzymes (PARP1, LIG3 and POLβ). Absence of Lmna led to accumulation of 8-oxoguanine (8-oxoG) lesions, and to an increased frequency of substitution mutations induced by chronic oxidative stress including GC>TA transversions (a fingerprint of 8-oxoG:A mismatches). Collectively, our results provide novel insights into the functional interplay between the nuclear lamina and cellular defenses against oxidative DNA damage, with implications for cancer and aging.

U2 - 10.1093/nar/gkz912

DO - 10.1093/nar/gkz912

M3 - Journal article

C2 - 31647095

SN - 0305-1048

JO - Nucleic Acids Research

JF - Nucleic Acids Research

ER -

Lamin A/C promotes DNA base excision repair

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