Somatic Hypermutation of Immunoglobulin Genes is Linked to Transcription

1998 ◽  
pp. 11-19 ◽  
Author(s):  
U. Storb ◽  
A. Peters ◽  
E. Klotz ◽  
N. Kim ◽  
H. M. Shen ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Immunoglobulin Genes

scholarly journals Identifying protein–protein interactions in somatic hypermutation

2005 ◽  
Vol 201 (4) ◽  
pp. 493-496 ◽  
Author(s):  
Myron F. Goodman ◽  
Matthew D. Scharff
Keyword(s):  
Mouse Model ◽  
Protein Interactions ◽  
Somatic Hypermutation ◽  
Model Systems ◽  
Antigen Binding ◽  
Immunoglobulin Genes ◽  
Protein Protein Interactions ◽  
Cell Systems ◽  
High Affinity ◽  
Key Players

Somatic hypermutation (SHM) in immunoglobulin genes is required for high affinity antibody–antigen binding. Cultured cell systems, mouse model systems, and human genetic deficiencies have been the key players in identifying likely SHM pathways, whereas “pure” biochemical approaches have been far less prominent, but change appears imminent. Here we comment on how, when, and why biochemistry is likely to emerge from the shadows and into the spotlight to elucidate how the somatic mutation of antibody variable (V) regions is generated.

Molecular Aspects of Somatic Hypermutation of Immunoglobulin Genes

1999 ◽  
Vol 64 (0) ◽  
pp. 227-234 ◽  
Author(s):  
U. STORB ◽  
A. PETERS ◽  
N. KIM ◽  
H.M. SHEN ◽  
G. BOZEK ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Immunoglobulin Genes ◽  
Molecular Aspects

scholarly journals The Concerted Action of Msh2 and UNG Stimulates Somatic Hypermutation at A · T Base Pairs

2009 ◽  
Vol 29 (18) ◽  
pp. 5148-5157 ◽  
Author(s):  
Darina Frieder ◽  
Mani Larijani ◽  
Cathy Collins ◽  
Marc Shulman ◽  
Alberto Martin
Keyword(s):  
Mismatch Repair ◽  
Essential Role ◽  
Somatic Hypermutation ◽  
Immunoglobulin Genes ◽  
Abasic Site ◽  
Mutation Load ◽  
Concerted Action ◽  
Base Pairs ◽  
Base Excision ◽  
Cytidine Deamination

ABSTRACT Mismatch repair plays an essential role in reducing the cellular mutation load. Paradoxically, proteins in this pathway produce A·T mutations during the somatic hypermutation of immunoglobulin genes. Although recent evidence implicates the translesional DNA polymerase η in producing these mutations, it is unknown how this or other translesional polymerases are recruited to immunoglobulin genes, since these enzymes are not normally utilized in conventional mismatch repair. In this report, we demonstrate that A·T mutations were closely associated with transversion mutations at a deoxycytidine. Furthermore, deficiency in uracil-N-glycolase (UNG) or mismatch repair reduced this association. These data reveal a previously unknown interaction between the base excision and mismatch repair pathways and indicate that an abasic site generated by UNG within the mismatch repair tract recruits an error-prone polymerase, which then introduces A·T mutations. Our analysis further indicates that repair tracts typically are ∼200 nucleotides long and that polymerase η makes ∼1 error per 300 T nucleotides. The concerted action of Msh2 and UNG in stimulating A·T mutations also may have implications for mutagenesis at sites of spontaneous cytidine deamination.

scholarly journals Apex2 is required for efficient somatic hypermutation but not for class switch recombination of immunoglobulin genes

2009 ◽  
Vol 21 (8) ◽  
pp. 947-955 ◽  
Author(s):  
Z. Sabouri ◽  
I.-m. Okazaki ◽  
R. Shinkura ◽  
N. Begum ◽  
H. Nagaoka ◽  
...  
Keyword(s):  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Immunoglobulin Genes ◽  
Class Switch

scholarly journals A new class of errant DNA polymerases provides candidates for somatic hypermutation

2001 ◽  
Vol 356 (1405) ◽  
pp. 47-51 ◽  
Author(s):  
Brigette Tippin ◽  
Myron F. Goodman
Keyword(s):  
Somatic Hypermutation ◽  
Dna Polymerases ◽  
Variable Region ◽  
Affinity Maturation ◽  
Immunoglobulin Genes ◽  
New Class ◽  
Eukaryotic Dna ◽  
Factor Governing

The mechanism of somatic hypermutation of the immunoglobulin genes remains a mystery after nearly 30 years of intensive research in the field. While many clues to the process have been discovered in terms of the genetic elements required in the immunoglobulin genes, the key enzymatic players that mediate the introduction of mutations into the variable region are unknown. The recent wave of newly discovered eukaryotic DNA polymerases have given a fresh supply of potential candidates and a renewed vigour in the search for the elusive mutator factor governing affinity maturation. In this paper, we discuss the relevant genetic and biochemical evidence known to date regarding both somatic hypermutation and the new DNA polymerases and address how the two fields can be brought together to identify the strongest candidates for further study. In particular we discuss evidence for the in vitro biochemical misincorporation properties of human Rad30B/Pol ι and how it compares to the in vivo somatic hypermutation spectra.

scholarly journals Somatic hypermutation targeting to intrinsic hotspots of immunoglobulin genes in follicular lymphoma and multiple myeloma

Leukemia ◽  
2001 ◽  
Vol 15 (11) ◽  
pp. 1772-1778 ◽  
Author(s):  
C Belessi ◽  
K Stamatopoulos ◽  
N Stavroyianni ◽  
K Zoi ◽  
T Papadaki ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Follicular Lymphoma ◽  
Somatic Hypermutation ◽  
Immunoglobulin Genes

Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 511-517 ◽  
Author(s):  
Pernille Andersen ◽  
Henrik Permin ◽  
Vagn Andersen ◽  
Lone Schejbel ◽  
Peter Garred ◽  
...  
Keyword(s):  
Tract Infection ◽  
Respiratory Tract ◽  
Respiratory Tract Infection ◽  
Light Chain ◽  
Common Variable Immunodeficiency ◽  
Somatic Hypermutation ◽  
Hot Spot ◽  
Reference Interval ◽  
Immunoglobulin Genes ◽  
Common Variable

AbstractReduced levels of somatic hypermutation (SHM) have recently been described in IgG-switched immunoglobulin genes in a minority of patients with common variable immunodeficiency (CVID), demonstrating a disruption of the normal linkage between isotype switch and SHM. To see if, irrespective of isotype, there is a tendency to use unmutated immunoglobulin genes in CVID, we studied SHM in κ light-chain transcripts using a VκA27-specific restriction enzyme-based hot-spot mutation assay (IgκREHMA). Hot-spot mutations were found in 48% (median; reference interval, 28%-62%) of transcripts from 53 healthy controls. Values were significantly lower in 31 patients (median, 7.5%; range, 0%-73%; P < .0000001) of whom 24 (77%) had levels below the reference interval. Low levels of SHM correlated with increased frequency of severe respiratory tract infection (SRTI; P < .005), but not with diarrhea (P = .8). Mannose-binding lectin (MBL) deficiency also correlated with SRTI score (P = .009). However, the correlation of SHM and SRTI was also seen when only patients with normal MBL genotypes were analyzed (n = 18, P = .006). A slight decline of mutated fractions over years was noted (P = .01). This suggests that most patients with CVID fail to recruit affinity-maturated B cells, adding a qualitative deficiency to the quantitative deficiency characterizing these patients.

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