Lamin A/C promotes DNA base excision repair

Author:

Maynard Scott1,Keijzers Guido2,Akbari Mansour2,Ezra Michael Ben2,Hall Arnaldur1,Morevati Marya2,Scheibye-Knudsen Morten2,Gonzalo Susana3,Bartek Jiri14,Bohr Vilhelm A25

Affiliation:

1. Danish Cancer Society Research Center, DK-2100 Copenhagen, Denmark

2. Department of Cellular and Molecular Medicine, Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen, Denmark

3. Department of Biochemistry and Molecular Biology, Saint Louis University, School of Medicine, Saint Louis, MO 63104, USA

4. Division of Genome Biology, Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, SE-17177 Stockholm, Sweden

5. Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA

Abstract

AbstractThe 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.

Funder

Danish Council for Independent Research

National Institutes of Health

Lundbeck Foundation

Danish Cancer Society

Publisher

Oxford University Press (OUP)

Subject

Genetics

Reference115 articles.

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