A role for the MutL mismatch repair Mlh3 protein in immunoglobulin class switch DNA recombination and somatic hypermutation.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Xiaoping WuPaolo Casali

Abstract

Class switch DNA recombination (CSR) and somatic hypermutation (SHM) are central to the maturation of the Ab response. Both processes involve DNA mismatch repair (MMR). MMR proteins are recruited to dU:dG mispairs generated by activation-induced cytidine deaminase-mediated deamination of dC residues, thereby promoting S-S region synapses and introduction of mismatches (mutations). The MutL homolog Mlh3 is the last complement of the mammalian set of MMR proteins. It is highly conserved in evolution and is essential to meiosis and microsatellite stability. We used the recently generated knockout mlh3(-/-) mice to address the role of Mlh3 in CSR and SHM. We found that Mlh3 deficiency alters both CSR and SHM. mlh3(-/-) B cells switched in vitro to IgG and IgA but displayed preferential targeting of the RGYW/WRCY (R = A or G, Y = C or T, W = A or T) motif by Sgamma1 and Sgamma3 breakpoints and introduced more insertions and fewer donor/acceptor microhomologies in Smu-Sgamma1 and Smu-Sgamma3 DNA junctions, as compared with mlh3(+/+) B cells. mlh3(-/-) mice showed only a slight decrease in the frequency of mutations in the intronic DNA downstream of the rearranged J(H)4 gene. However, the residual mutations were altered in spectrum. T...Continue Reading

References

Sep 1, 1995·Nature Genetics·A H ReitmairB Liu
Jun 28, 1996·Cell·W EdelmannR Kucherlapati
Jul 1, 1996·The Journal of Experimental Medicine·P D HodgkinA B Lyons
Mar 21, 1998·Science·M CascalhoM Wabl
Jun 17, 1998·Proceedings of the National Academy of Sciences of the United States of America·D B WinterP J Gearhart
Oct 15, 1998·Proceedings of the National Academy of Sciences of the United States of America·H Flores-Rozas, R D Kolodner
Jan 23, 1999·Nature Genetics·W EdelmannR Kucherlapati
Aug 3, 1999·The Journal of Experimental Medicine·C E SchraderJ Stavnezer
Dec 30, 1999·Nature Genetics·J Jiricny
Feb 26, 2000·Annual Review of Genetics·A B BuermeyerR M Liskay
Nov 28, 2000·Annual Review of Genetics·B D Harfe, S Jinks-Robertson
May 29, 2001·Nature Immunology·I B RogozinT A Kunkel
Nov 22, 2001·Proceedings of the National Academy of Sciences of the United States of America·M R EhrensteinM S Neuberger
Mar 1, 2002·Current Opinion in Immunology·Marilyn Diaz, Paolo Casali
Mar 26, 2002·Nature Genetics·Joachim KloseHans Lehrach
May 1, 2002·European Journal of Immunology·Qiang PanLennart Hammarström
May 8, 2002·The Journal of Experimental Medicine·Linda BrossHeinz Jacobs
May 8, 2002·The Journal of Experimental Medicine·F Nina Papavasiliou, David G Schatz
Jul 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Youri I PavlovThomas A Kunkel
May 14, 2003·The Journal of Experimental Medicine·Carol E SchraderJanet Stavnezer
Jun 27, 2003·Trends in Biochemical Sciences·Michael S NeubergerSvend K Petersen-Mahrt
Aug 20, 2003·The Journal of Experimental Medicine·John P McDonaldPatricia J Gearhart
Sep 10, 2003·Journal of Clinical Immunology·Xiaoping WuPaolo Casali

❮ Previous
Next ❯

Citations

Aug 24, 2010·Nature Structural & Molecular Biology·Zhenming XuPaolo Casali
Mar 3, 2007·Annual Review of Biochemistry·Javier M Di Noia, Michael S Neuberger
Sep 19, 2006·World Journal of Gastroenterology : WJG·Hong-Xu LiuJun Yang
Apr 6, 2007·Proceedings of the National Academy of Sciences of the United States of America·Hideharu SekineTimothy W Behrens
Oct 16, 2008·Proceedings of the National Academy of Sciences of the United States of America·Sergio RoaMatthew D Scharff
Jun 26, 2012·Nature Reviews. Immunology·Zhenming XuPaolo Casali
Jul 30, 2010·Mutation Research·Yaroslava Y Polosina, Claire G Cupples
Nov 22, 2011·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Richard ChahwanSergio Roa

❮ Previous
Next ❯

Related Concepts

Related Feeds

Ataxia telangiectasia (MDS)

Ataxia telangiectasia is a rare neurodegenerative diseases caused by defects in the ATM gene, which is involved in DNA damage recognition and repair pathways. Here is the latest research on this autosomal recessive disease.