In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 4551-4551
Abstract:
Over 3 billion base pairs of a mammalian cell have to be replicated with every cell division. Limitations in the supply of nucleotides and DNA lesions slow down replication fork speed and trigger a complex replicative stress response to prevent genomic instability and cancer development. The checkpoint kinases ataxia telangiectasia mutated (ATM), ATM and Rad3-related (ATR), checkpoint kinase-1 (CHK1), and checkpoint kinase-2 (CHK2) are at the heart of this response. These factors catalyze processes that slow down the cell cycle as well as mechanisms that stabilize the replication fork and processes that initiate DNA repair. Such pathways ensure the faithful transmission of DNA without epigenetic alterations and DNA mutations. As expected for such a pivotal mechanism, checkpoint kinase signaling is highly regulated. Posttranslational modifications including phosphorylation and acetylation regulate checkpoint kinases at multiple levels. Recent data show that class I histone deacetylases (HDACs) can affect checkpoint kinase signaling and genomic stability. How these HDACs control checkpoint kinases exactly and if they show specificity for certain checkpoint kinases and DNA repair pathways has not been resolved. Moreover, although it is known that phosphorylation triggers checkpoint kinase activation and that the trimeric phosphatase PP2A attenuates checkpoint kinase phosphorylation it is unknown how this activity of PP2A is modulated. PP2A consists of the subunits A (structural component, PPP2R1A/B), C (catalytic activity, PPP2CA/B), and B (discriminates between substrates to allow specificity of the PP2A holoenzyme). Our data illustrate that class I HDACs are required for checkpoint kinase phosphorylation in human and murine cells. We show that these enzymes suppress the expression of certain PP2A subunits and we reveal that one of the B type subunits specifically targets checkpoint kinases for dephosphorylation by the PP2A holoenzyme. With genetic and biochemical approaches, including RNAi, CRISPR-Cas9, DNA fiber assays, confocal microscopy, and DNA and protein analyses, we demonstrate how these mechanisms maintain S phase arrest and the survival of cells undergoing replicative stress. Citation Format: Anja Göder, Claudia Schäfer, Teodora Nikolova, Günter Schneider, Oliver H. Krämer. Regulation of replicative stress by deacetylation and dephosphorylation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4551.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2016-4551
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2016
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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