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Cell Rep. 2015 Nov 17;13(7):1396-1406. doi: 10.1016/j.celrep.2015.10.006. Epub 2015 Nov 5.

Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair.

Author information

1
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong; Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen 518000, China.
2
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong; School of Medicine, Shenzhen University, Shenzhen 518060, China.
3
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong.
4
School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong; Shenzhen Institute of Innovation and Research, The University of Hong Kong, Nanshan, Shenzhen 518000, China. Electronic address: zhongjun@hku.hk.

Abstract

The nuclear lamins are essential for various molecular events in the nucleus, such as chromatin organization, DNA replication, and provision of mechanical support. A specific point mutation in the LMNA gene creates a truncated prelamin A termed progerin, causing Hutchinson-Gilford progeria syndrome (HGPS). SIRT6 deficiency leads to defective genomic maintenance and accelerated aging similar to HGPS, suggesting a potential link between lamin A and SIRT6. Here, we report that lamin A is an endogenous activator of SIRT6 and facilitates chromatin localization of SIRT6 upon DNA damage. Lamin A promotes SIRT6-dependent DNA-PKcs (DNA-PK catalytic subunit) recruitment to chromatin, CtIP deacetylation, and PARP1 mono-ADP ribosylation in response to DNA damage. The presence of progerin jeopardizes SIRT6 activation and compromises SIRT6-mediated molecular events in response to DNA damage. These data reveal a critical role for lamin A in regulating SIRT6 activities, suggesting that defects in SIRT6 functions contribute to impaired DNA repair and accelerated aging in HGPS.

PMID:
26549451
DOI:
10.1016/j.celrep.2015.10.006
[Indexed for MEDLINE]
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