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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • DNA Damage
  • DNA Repair*
  • DNA-Activated Protein Kinase / metabolism
  • Enzyme Activation
  • HEK293 Cells
  • Humans
  • Lamin Type A / physiology*
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Transport
  • Sirtuins / chemistry
  • Sirtuins / metabolism*


  • Lamin Type A
  • DNA-Activated Protein Kinase
  • SIRT6 protein, human
  • Sirtuins