title: Lamin A Is an Endogenous SIRT6 Activator and Promotes SIRT6-Mediated DNA Repair.
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.
authors.affiliation: 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.
authors.forename: Shrestha
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: 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.
authors.forename: Baohua
authors.initials: B
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong.
authors.forename: Yi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, 21 Sassoon Road, Pok Fu Lam, Hong Kong.
authors.forename: Quan
authors.initials: Q
authors.lastname: Hao
authors.affiliation: 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.
authors.forename: Zhongjun
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D004249:DNA Damage; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004789:Enzyme Activation; D057809:HEK293 Cells; D006801:Humans; D034904:Lamin Type A / Q000502:physiology*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D021381:Protein Transport; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D051747:DNA-Activated Protein Kinase; C516592:SIRT6 protein, human; D037761:Sirtuins