Lamin A/C promotes DNA base excision repair
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Lamin A/C promotes DNA base excision repair. / Maynard, Scott; Keijzers, Guido; Akbari, Mansour; Ezra, Michael Ben; Hall, Arnaldur; Morevati, Marya; Scheibye-Knudsen, Morten; Gonzalo, Susana; Bartek, Jiri; Bohr, Vilhelm A.
In: Nucleic Acids Research, Vol. 47, No. 22, 2019, p. 11709–11728.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
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
Y1 - 2019
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
VL - 47
SP - 11709
EP - 11728
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 22
ER -
ID: 229437597