The Biochemistry of Somatic Hypermutation

Peled, Jonathan U.; Kuang, Fei Li; Iglesias-Ussel, Maria D.; Roa, Sergio; Kalis, Susan L.; Goodman, Myron F.; Scharff, Matthew D.

doi:10.1146/annurev.immunol.26.021607.090236

Cited by 410 publications

(475 citation statements)

References 173 publications

Supporting

Mentioning

456

Contrasting

Unclassified

Order By: Relevance

“…31 If the mutations were randomly generated, one would expect a 1:2 transition/transversion ratio. Indeed, in DLBCL samples, the transition/transversion ratio was inverted (343/241, 1.42:1), thus demonstrating a clear enrichment for transitions (P ¼ 4.07 Â 10 À18 ) supporting previous reports 8 that BCL2 mutations likely occurred as a result of SHM.…”

Section: Resultsmentioning

confidence: 99%

BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

View full text Add to dashboard Cite

BCL2 is deregulated in diffuse large B-cell lymphoma (DLBCL) by the t(14;18) translocation, gene amplification and/or nuclear factor-kB signaling. RNA-seq data have recently shown that BCL2 is the most highly mutated gene in germinal center B-cell (GCB) DLBCL. We have sequenced BCL2 in 298 primary DLBCL biopsies, 131 additional non-Hodgkin lymphoma biopsies, 24 DLBCL cell lines and 51 germline DNAs. We found frequent BCL2 mutations in follicular lymphoma (FL) and GCB DLBCL, but low levels of BCL2 mutations in activated B-cell DLBCL, mantle cell lymphoma, small lymphocytic leukemia and peripheral T-cell lymphoma. We found no BCL2 mutations in GC centroblasts. Many mutations were non-synonymous; they were preferentially located in the flexible loop domain, with few in BCL2-homology domains. An elevated transition/transversions ratio supports that the mutations result from somatic hypermutation. BCL2 translocations correlate with, and are likely important in acquisition of, additional BCL2 mutations in GCB DLBCL and FL. DLBCL mutations were not independently associated with survival. Although previous studies of BCL2 mutations in FL have reported mutations to result in pseudo-negative BCL2 protein expression, we find this rare in de-novo DLBCL.Leukemia ( BCL2, discovered because of its involvement in t(14;18) in follicular lymphoma (FL), 3 has a central role in the inhibition of apoptosis. 4 BCL2 is normally transiently expressed during B-cell maturation. The t(14;18) translocation causes constitutive overexpression of BCL2 by juxtaposing it to immunoglobulin heavy chain gene enhancer elements. This translocation is found in B20% of DLBCL, 5 most often in the GCB subtype of DLBCL. 6 Other mechanisms of BCL2 deregulation, more often observed in ABC DLBCLs, include amplification of the BCL2 gene or its transcriptional upregulation through constitutive activation of the nuclear factor-kB pathway. 7 Saito et al. 8 reported that the BCL2 promoter can also be aberrantly hypermutated in DLBCL, which may prevent its inhibition by MIZ1 and BCL6. 8 They found a high number of mutations in BCL2 and suggested that the mutations described were the result of somatic hypermutation (SHM). Mutations in BCL2 have been shown to cause false-negative protein expression results in immunohistochemistry assays in FL; 9,10 however, no large study has so far investigated whether this occurs in DLBCL.

show abstract

Section: Resultsmentioning

confidence: 99%

BCL2 mutations in diffuse large B-cell lymphoma

et al. 2011

View full text Add to dashboard Cite

show abstract

“…AID acts as a mutator by deaminating deoxycytidine in single stranded DNA thereby changing the base, cytosine, into a uracil (reviewed in 3 ). Through further processing by DNA repair enzymes that recognize uracil in DNA, this single biochemical activity triggers different genetic modifications that are critical for a proper antibody response (reviewed in 3,4 ).…”

Section: Introductionmentioning

confidence: 99%

“…AID also initiates class switch recombination (CSR), which exchanges the exons encoding the Fc region of the antibody from the default IgM to another isotype 1,2 . All the known components in these pathways except for AID are ubiquitous DNA repair enzymes (reviewed in [3][4][5] ). Indeed, AID is able to trigger SHM and CSR in non-B cell models 6,7 and since such mutagenic and recombinogenic enzyme is potentially dangerous, it needs to be tightly regulated.…”

Section: Introductionmentioning

confidence: 99%

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Patenaude

Orthwein

et al. 2009

Nat Struct Mol Biol

134

175

View full text Add to dashboard Cite

The enzyme Activation Induced Deaminase (AID) triggers antibody diversification in B-cells by catalyzing deamination and consequently mutation of immunoglobulin genes. To minimize off-target deamination, AID is restrained by several regulatory mechanisms including nuclear exclusion, thought to be mediated exclusively by active nuclear export. Here we identify two other mechanisms involved in controlling AID subcellular localization. AID is unable to passively diffuse into the nucleus, despite its small size, its nuclear entry requiring active import mediated by a conformational nuclear localization sequence (NLS). We also identify a determinant for AID cytoplasmic retention in its Cterminus, which hampers diffusion to the nucleus, competes with nuclear import and is critical for maintaining the predominantly cytoplasmic localization of AID in steady-state conditions. Blocking nuclear import alters the balance between these processes in favor of cytoplasmic retention, resulting in reduced isotype class switching.3

show abstract

“…The finding that the latter steps require also MMR proteins came as a surprise, given that MMR has hitherto been believed to be an error-free rather than an error-prone pathway. As a number of reviews on the subject are available [37][38][39], we shall focus solely on the mechanistic aspects of the processes and on the possible involvement of MMR proteins in them.…”

Section: Mmr Proteins In Antibody Maturationmentioning

confidence: 99%

“…But about 50% of mutations linked to SHM and CSR arise at T/A base pairs, i.e. at sites not deaminated by AID, and it is this subset of mutations that has been genetically linked to MMR (primarily to MSH2, MSH6 and EXO1) and to the translesion DNA polymerases pol-ζ and pol-η [37][38][39]. It has been proposed that processing of the AID-generated U/G mispairs by MMR would give rise to long repair tracts that might be filled-in by error-prone polymerases to generate the observed mutations.…”

Section: Mmr Proteins In Antibody Maturationmentioning

confidence: 99%

Mammalian mismatch repair: error-free or error-prone?

Peña-Dı́az

Jiricny

2012

Trends in Biochemical Sciences

102

View full text Add to dashboard Cite

A considerable surge of interest in the mismatch repair (MMR) system has been brought about by the discovery of a link between Lynch syndrome, an inherited predisposition to cancer of the colon and other organs, and malfunction of this key DNA metabolic pathway. This review focuses on recent advances in our understanding of the molecular mechanisms of canonical MMR, which improves replication fidelity by removing misincorporated nucleotides from the nascent DNA strand. We also discuss the involvement of MMR proteins in two other processes: trinucleotide repeat expansion and antibody maturation, in which MMR proteins are required for mutagenesis rather than for its prevention. 3

show abstract

The Biochemistry of Somatic Hypermutation

Cited by 410 publications

References 173 publications

BCL2 mutations in diffuse large B-cell lymphoma

BCL2 mutations in diffuse large B-cell lymphoma

Active nuclear import and cytoplasmic retention of activation-induced deaminase

Mammalian mismatch repair: error-free or error-prone?

Contact Info

Product

Resources

About