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Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates
14:32

Deacetylation Assays to Unravel the Interplay between Sirtuins (SIRT2) and Specific Protein-substrates

Published on: February 27, 2016

SIRT2 directs the replication stress response through CDK9 deacetylation

Hui Zhang1, Seong-Hoon Park, Brooke G Pantazides

  • 1Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.

Proceedings of the National Academy of Sciences of the United States of America
|July 31, 2013
PubMed

Insights

Sirtuin 2 (SIRT2) regulates DNA replication stress responses by deacetylating cyclin-dependent kinase 9 (CDK9). This deacetylation stimulates CDK9 activity, promoting cell recovery and maintaining genome integrity, highlighting SIRT2's tumor suppressor role.

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Genetics

Background:

  • Sirtuin 2 (SIRT2) is a deacetylase involved in acetylome signaling and genome integrity.
  • SIRT2 functions as a tumor suppressor in mice.
  • Replication stress responses are critical for maintaining genomic stability.

Purpose of the Study:

  • To investigate the role of SIRT2 in regulating DNA replication stress responses.
  • To elucidate the mechanism by which SIRT2 controls recovery from replication arrest.
  • To define SIRT2's function in maintaining genome integrity and its tumor suppressor activity.

Main Methods:

  • Investigated SIRT2's role in replication stress responses using SIRT2-deficient models.
  • Analyzed the interaction and deacetylation of cyclin-dependent kinase 9 (CDK9) by SIRT2.
  • Assessed the impact of CDK9 acetylation status on replication stress recovery.

Main Results:

  • SIRT2 deficiency leads to sensitivity to replication stress and impaired recovery from arrest.
  • SIRT2 deacetylates CDK9 at lysine 48, enhancing its kinase activity and promoting recovery.
  • Wild-type CDK9, but not acetylated CDK9, rescues the replication stress defects in SIRT2-deficient cells.

Conclusions:

  • SIRT2 regulates replication stress responses by deacetylating CDK9, thereby stimulating its kinase activity.
  • This SIRT2-CDK9 interaction is crucial for recovery from replication arrest and maintaining genome integrity.
  • SIRT2's function in regulating these checkpoint pathways provides a mechanism for its tumor suppressor activity.
Keywords:
DNA damagecell cycle checkpointgenome maintenance

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