HLTF and SHPRH are not essential for PCNA polyubiquitination, survival and somatic hypermutation: Existence of an alternative E3 ligase

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

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

50 Citaten (Scopus)

Samenvatting

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-Ubn) 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 PCNAK164R 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-Ubn in mammals. As PCNA-Ub and PCNA-Ubn both make use of K164, error-free PCNA-Ubn-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-Ubn is prohibited in PCNAK164R MEFs, the formation of PCNA-Ubn 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-Ubn.

Originele taal-2Engels
Pagina's (van-tot)438-444
Aantal pagina's7
TijdschriftDNA Repair
Volume10
Nummer van het tijdschrift4
DOI's
StatusGepubliceerd - 3 apr. 2011
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'HLTF and SHPRH are not essential for PCNA polyubiquitination, survival and somatic hypermutation: Existence of an alternative E3 ligase'. Samen vormen ze een unieke vingerafdruk.

Citeer dit