Cited by 153DNA Repair MechanismsGenomics and Chromatin DynamicsNuclear Structure and Function

The ATM Substrate KAP1 Controls DNA Repair in Heterochromatin: Regulation by HP1 Proteins and Serine 473/824 Phosphorylation

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White, David, Rafalska-Metcalf, Ilona U., Ivanov, Alexey V., Corsinotti, Andrea, Peng, Hongzhuang, Lee, Sheng-Chung, Trono, Didier, Janicki, Susan M. +1 more·2012·Molecular Cancer Research

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Abstract

The repair of DNA damage in highly compact, transcriptionally silent heterochromatin requires that repair and chromatin packaging machineries be tightly coupled and regulated. KAP1 is a heterochromatin protein and co-repressor that binds to HP1 during gene silencing but is also robustly phosphorylated by Ataxia telangiectasia mutated (ATM) at serine 824 in response to DNA damage. The interplay between HP1-KAP1 binding/ATM phosphorylation during DNA repair is not known. We show that HP1α and unmodified KAP1 are enriched in endogenous heterochromatic loci and at a silent transgene prior to damage. Following damage, γH2AX and pKAP1-s824 rapidly increase and persist at these loci. Cells that lack HP1 fail to form discreet pKAP1-s824 foci after damage but levels are higher and more persistent. KAP1 is phosphorylated at serine 473 in response to DNA damage and its levels are also modulated by HP1. Unlike pKAP1-s824, pKAP1-s473 does not accumulate at damage foci but is diffusely localized in the nucleus. While HP1 association tempers KAP1 phosphorylation, this interaction also slows the resolution of γH2AX foci. Thus, HP1-dependent regulation of KAP1 influences DNA repair in heterochromatin. Mol Cancer Res; 10(3); 401–14. ©2011 AACR.

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  • Post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in.

    “post-translational modification of KAP1 plays a critical role in determining which cellular context the protein will function in; for example sumoylated KAP1 promotes regulation of gene expression, while phosphorylated KAP1 promotes DNA repair41,42.”

    From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [42]

    The Discussion (page unavailable) links KAP1 Ser 824 phosphorylation to effective DNA repair in heterochromatin, supporting the phosphorylation example. The paper also discusses KAP1-mediated gene silencing, but its text does not establish the sentence’s specific claim that sumoylated KAP1 regulates gene expression or that modifications determine mutually distinct functions; it reports that gene-silencing activity does not diminish in irradiated cells. (LLM, conf=0.85)

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  • SIRT6 co-occupies approximately 10% of KAP1-bound promoters.

    “analysis of promoter arrays41,42 showed that SIRT6 only co-occupies approximately 10% of KAP1 bound promoters”

    From SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age (2014) · cites this paper as [42]

    The Results passages discuss KAP1 with HP1 at a transgene array and KAP1 phosphorylation after DNA damage, not promoter occupancy. Searches for SIRT6, promoter arrays, and the approximately 10% overlap found no passage in our copy addressing the claim. (LLM, conf=0.75)

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Authors
White, D., Rafalska-Metcalf, I. U., Ivanov, A. V., Corsinotti, A., Peng, H., Lee, S.-C., Trono, D., Janicki, S. M., & Rauscher, F. J.
Affiliations
The Wistar Institute (US)
Corresponding author
Rauscher, Frank J.
Venue
Molecular Cancer Research
Published
2012-03-01
Volume
10
Issue
3
Pages
401-414
ISSN
  • 1541-7786 (ISSN-L)
  • 1557-3125
OpenAlex
W2100197820
Cited by
152
References
37
Citations by year
2026: 11 · 2025: 12 · 2024: 15 · 2023: 9 · 2022: 7 · 2021: 14 · 2020: 9 · 2019: 8 · 2018: 8 · 2017: 12 · 2016: 11 · 2015: 14 · 2014: 13 · 2013: 4 · 2012: 3
FWCI
2.60
Type
journal article
Language
en
Open access
Locations
  • Molecular Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
  • Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
Funders
  • National Cancer Institute (R01CA129833, CA010815, CA129833, CA126283, F32CA126283, P30CA010815)
  • National Center for Research Resources (P20 RR16440, P20RR016440)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
KAP1, ATM, HP1, heterochromatin, DNA repair, γH2AX foci, gene silencing, chromatin condensation, DNA damage response
MeSH terms
Tripartite Motif-Containing Protein 28, Chromobox Protein Homolog 5, Amino Acid Sequence, Animals, Cell Fractionation, Chromosomal Proteins, Non-Histone, DNA Repair, DNA-Binding Proteins, Heterochromatin, Histones, Humans, Immunohistochemistry, Models, Biological, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Phosphoserine, Repressor Proteins, Substrate Specificity, Blotting, Western, Protein Serine-Threonine Kinases, Cell Cycle Proteins, Transgenes, Tumor Suppressor Proteins, NIH 3T3 Cells, Mutant Proteins, Mice, Gene Knockdown Techniques, Ataxia Telangiectasia Mutated Proteins

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