Document Detail

HLTF and SHPRH are not essential for PCNA polyubiquitination, survival and somatic hypermutation: existence of an alternative E3 ligase.
MedLine Citation:
PMID:  21269891     Owner:  NLM     Status:  MEDLINE    
DNA damage tolerance is regulated at least in part at the level of proliferating cell nuclear antigen (PCNA) ubiquitination. Monoubiquitination (PCNA-Ub) at lysine residue 164 (K164) stimulates error-prone translesion synthesis (TLS), Rad5-dependent polyubiquitination (PCNA-Ub(n)) stimulates error-free template switching (TS). To generate high affinity antibodies by somatic hypermutation (SHM), B cells profit from error-prone TLS polymerases. Consistent with the role of PCNA-Ub in stimulating TLS, hypermutated B cells of PCNA(K164R) mutant mice display a defect in generating selective point mutations. Two Rad5 orthologs, HLTF and SHPRH have been identified as alternative E3 ligases generating PCNA-Ub(n) in mammals. As PCNA-Ub and PCNA-Ub(n) both make use of K164, error-free PCNA-Ub(n)-dependent TS may suppress error-prone PCNA-Ub-dependent TLS. To determine a regulatory role of Shprh and Hltf in SHM, we generated Shprh/Hltf double mutant mice. Interestingly, while the formation of PCNA-Ub and PCNA-Ub(n) is prohibited in PCNA(K164R) MEFs, the formation of PCNA-Ub(n) is not abolished in Shprh/Hltf mutant MEFs. In line with these observations Shprh/Hltf double mutant B cells were not hypersensitive to DNA damage. Furthermore, SHM was normal in Shprh/Hltf mutant B cells. These data suggest the existence of an alternative E3 ligase in the generation of PCNA-Ub(n).
Peter H L Krijger; Kyoo-Young Lee; Niek Wit; Paul C M van den Berk; Xiaoli Wu; Henk P Roest; Alex Maas; Hao Ding; Jan H J Hoeijmakers; Kyungjae Myung; Heinz Jacobs
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2011-01-26
Journal Detail:
Title:  DNA repair     Volume:  10     ISSN:  1568-7856     ISO Abbreviation:  DNA Repair (Amst.)     Publication Date:  2011 Apr 
Date Detail:
Created Date:  2011-03-22     Completed Date:  2011-07-01     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  101139138     Medline TA:  DNA Repair (Amst)     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  438-44     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier B.V. All rights reserved.
Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
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MeSH Terms
B-Lymphocytes / drug effects,  metabolism
Cell Survival / drug effects,  genetics,  radiation effects
Cross-Linking Reagents / pharmacology
DNA Helicases / deficiency,  genetics,  metabolism*
Embryonic Stem Cells / metabolism
Gene Knockdown Techniques
Gene Order
Gene Targeting
Immunoglobulin Class Switching / drug effects
Lipopolysaccharides / pharmacology
Mice, Knockout
Proliferating Cell Nuclear Antigen / genetics,  metabolism*
Somatic Hypermutation, Immunoglobulin / genetics*
Transcription Factors / deficiency,  genetics,  metabolism*
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination / genetics,  physiology*,  radiation effects
Ultraviolet Rays / adverse effects
Grant Support
Reg. No./Substance:
0/Cross-Linking Reagents; 0/Lipopolysaccharides; 0/Proliferating Cell Nuclear Antigen; 0/Transcription Factors; EC 3.6.1.-/DNA Helicases; EC Ligases

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