|Genomic instability: Ada3 and HPV E6-acetyltransferase connections?|
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|PMID: 23255094 Owner: NLM Status: Publisher|
|Comment on: Mirza S, et al. Cell Cycle 2012; 11:4266-74.|
|Elliot J Androphy|
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|Type: JOURNAL ARTICLE Date: 2012-12-19|
|Title: Cell cycle (Georgetown, Tex.) Volume: 12 ISSN: 1551-4005 ISO Abbreviation: Cell Cycle Publication Date: 2012 Dec|
|Created Date: 2012-12-20 Completed Date: - Revised Date: -|
Medline Journal Info:
|Nlm Unique ID: 101137841 Medline TA: Cell Cycle Country: -|
|Languages: ENG Pagination: - Citation Subset: -|
|Department of Dermatology; Indiana University School of Medicine; Indianapolis, IN USA.|
|APA/MLA Format Download EndNote Download BibTex|
Journal ID (nlm-ta): Cell Cycle
Journal ID (iso-abbrev): Cell Cycle
Journal ID (publisher-id): CC
Publisher: Landes Bioscience
Copyright © 2013 Landes Bioscience
Print publication date: Day: 01 Month: 1 Year: 2013
pmc-release publication date: Day: 01 Month: 1 Year: 2013
Volume: 12 Issue: 1
First Page: 13 Last Page: 13
PubMed Id: 23255094
Publisher Id: 2012NV0851
Publisher Item Identifier: 23172
|Genomic instability : Ada3 and HPV E6-acetyltransferase connections?|
|Elliot J. Androphy|
|Department of Dermatology; Indiana University School of Medicine; Indianapolis, IN USA
|Correspondence: Correspondence to: Elliot J. Androphy; Email: firstname.lastname@example.org
DNA damage induced by chemicals or radiation must be detected, checkpoints activated, repair enzymes induced and recruited to the lesion and DNA crosslinks and breaks resolved. Because genotoxic damage can eventuate in cell cycle arrest, senescence or death, a tightly organized cascade of complex events must ensue. How DNA damage signals induce these very different outcomes remains to be precisely determined. Two mechanisms, non-homologous end-joining and homologous recombination, are available for restoration of DNA integrity. We know many of the players, yet how these proteins are integrated in the cellular response is a tangle of protein-protein interactions.
Two manuscripts1,2 from Vimla Band’s group report the consequences of disrupting the murine Ada3 gene. Loss of Ada3 increased basal phosphorylation of several key DNA damage pathway factors, including ATM and γH2AX. Ada3-null cells exhibited a prolonged response to irradiation and a variety of chromosomal alterations indicative of ineffective DNA repair.
What is the operative mechanism? The 432-amino acid Ada3 protein has attributes of a signal integrator. The C-terminal half of Ada3 binds to lysine acetyltransferases (KATs) that acetylate histones, also referred to as HATs, which influence local chromatin structure. KATs also interact with a host of key regulatory factors, including p53, the tumor suppressor that controls cell fate decisions following genotoxic stress. The N-terminal domain of Ada3 binds p53. Ada3 modulates acetylation of C-terminal lysines in p53 that are necessary for p14ARF signaling to p53 for induction cell senescence.3 The activation status of p53, including specific acetylation and phosphorylation sites, following homozygous Ada3 deletion in mouse tissues was not reported. Inability to activate p53 and induce its effector functions might lead to the observed accumulation of DNA damage and genetic instability. Nonetheless, p53 is not the sole determinant of Ada3 function. Homozygous deletion of Ada3 is embryonic lethal,2 while p53 nullizygous mice are viable. Ada3 haploinsufficent mice were not reported to have increased tumor development.
Several KAT proteins are involved in control of DNA repair. The Band laboratory reported the KAT family members p300, PCAF and GCN5 co-immunoprecipitate with Ada3.4 GCN5 in conjunction with E2F1 was found to stimulate recruitment of excision repair factors following UV radiation.5 Although not reported to associate with Ada3, the KAT protein Tip60 is an intriguing possibility, as its acetyltransferase activity is rapidly stimulated upon irradiation and, together with the mre11-rad50-nbs (MRN) complex, increased ATM kinase activity in response to double-stranded DNA breaks.6 Another consequence of Ada3 absence is stalling of cell cycle progression from G1 and accumulation of the cdk inhibitor p27Kip1.2 There was concomitant reduction in the levels of p300 and PCAF. PCAF, but not p300/CBP, regulates expression of the cell cycle regulator p21cip1. Because Ada3-deficient cells accumulate at G1/S, might Ada3 and its associated histone acetyltransferases be required for modifying chromatin structure at origins of DNA replication or for resolution of DNA damage that occurs during strand separation and synthesis? Clearly the interaction of Ada3 and KAT proteins in the DNA damage response deserves further investigation.
The relationship between genetic abnormalities accompanying Ada3 deficiency to the viral oncoprotein HPV E6 are provocative. The cervical cancer-associated HPV types 16 and 18 E6 proteins bind to and inactivate Ada3, which correlates with the ability to immortalize human epithelial cells and HPV 16 E6 mutants that retain binding to Ada3 inhibit p53 acetylation.7 Mechanistically, E6 could interfere with binding of p53 or a KAT to Ada3, although this remains to be shown. HPV 18 E6 also induces degradation of Tip60, which may result in inability to induce DNA repair mechanisms.8 Interestingly, E6 proteins from HPV types associated with cutaneous cancers were found to stimulate p300 degradation, inhibit expression of the DNA repair factor ATR and leading to persistence of UV-induced thymine dimers.9 Nonetheless, cell lines expressing HPV are remarkably stable and do not accumulate chromosomal damage observed in Ada3-knockout cells.
Does Ada3 complex with specific DNA damage pathway proteins? Sorting out the functions of Ada3, HPV E6, the relevant HAT proteins and their targets will be most informative.
Previously published online: www.landesbioscience.com/journals/cc/article/23172
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|4.||Germaniuk-Kurowska A,et al. Cancer ResYear: 200767117899710.1158/0008-5472.CAN-07-272118089809|
|5.||Guo R,et al. Nucleic Acids ResYear: 2011391390710.1093/nar/gkq98320972224|
|6.||Sun Y,et al. Cell CycleYear: 20109930610.4161/cc.9.5.1093120160506|
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Keywords: Keywords: Ada3, DNA damage, HPV E6, acetyltransferase, HAT, genomic instability.
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