Mechanism of somatic hypermutation: Critical analysis of strand biased mutation signatures at A:T and G:C base pairs

Steele, Edward J.

doi:10.1016/j.molimm.2008.10.021

Cited by 42 publications

(90 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this, we found no difference among genotypes in the frequency of dinucleotide substitutions (P ≥ 0.84) or a decreased ratio of mutations in A as opposed to T (P ≥ 0.45). In fact, Pms2 −/− and Pms2 EK/EK mice retained the strand bias signature previously attributed to the error-prone polymerase Pol η (29,30), in which mutations at A sites and WA motifs exceed mutations at T sites and TW motifs. Furthermore, the overall mutation frequencies of the hotspots for AID (WRC/GYW) and Pol η (WA/TW), which are major hallmarks of the SHM process, were similar in WT, null, and mutant mice (P ≥ 0.17).…”

Section: (F) Thementioning

confidence: 53%

“…Considering the possibility that other factors (e.g., MLH3 or apurinic/apyrimidinic endonuclease) might efficiently compensate for the absence of PMS2 and fulfill the endonucleolytic requirements of V-region hypermutation, we investigated SHM in our mutant mice. Pms2 EK/EK , Pms2 −/− and WT mice were immunized with NP 30 -CGG, and splenic B cells were analyzed for the …”

Section: Resultsmentioning

confidence: 99%

“…Eight-week-old mice were immunized i.p. with (4-hydroxy-3-nitrophenyl)acetyl (NP) 30 -CGG (BioSearch Technologies) in alum (Pierce) and boosted 4 wk later. TRIzol extraction (Invitrogen) of RNA was prepared 7 d after the boost from splenic B cells.…”

Section: Methodsmentioning

confidence: 99%

“…The experimental error rate was estimated 2.2 × 10 −4 mutations/base by analysis of the Cγ1 segment. A significant bias of mutations from A exceeding mutations from T in the WT data was used for quality assessment of contaminating PCR hybrids, as suggested recently (30).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

Oers

Roa

Werling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The DNA mismatch repair protein PMS2 was recently found to encode a novel endonuclease activity. To determine the biological functions of this activity in mammals, we generated endonuclease-deficient Pms2 E702K knock-in mice. Pms2 EK/EK mice displayed increased genomic mutation rates and a strong cancer predisposition. In addition, class switch recombination, but not somatic hypermutation, was impaired in Pms2 EK/EK B cells, indicating a specific role in Ig diversity. In contrast to Pms2 −/− mice, Pms2 EK/EK male mice were fertile, indicating that this activity is dispensable in spermatogenesis. Therefore, the PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance and tumor suppression.DNA mismatch repair | B cell lymphoma | class switch recombination | somatic hypermutation | spermatogenesis P MS2 is an essential component of DNA mismatch repair (MMR) complexes, which play an important role in maintaining genetic stability. MMR functions primarily in the detection and repair of mismatched bases that result from erroneous replication, and also plays important roles in DNA damage response, genetic recombination, control of meiotic progression, and generation of antibody diversity (1). During MMR, heterodimeric MutS homolog (MSH) complexes, consisting of either MSH2 and MSH6 (MutSα) or MSH2 and MSH3 (MutSβ), bind to mismatched bases. On binding, a conformational change in the MutS complexes activates downstream events and leads to the recruitment of MutL homolog (MLH) complexes consisting of either MLH1 and PMS2 (MutLα) or MLH1 and MLH3 (MutLγ). MutLα interacts with the MutS complexes via MLH1, and this interaction is essential for the coordination of downstream repair events, including excision of the mismatch carrying strand and its resynthesis (2, 3).Important insights into the role of MutLα in MMR came from biochemical studies of reconstituted human MMR (4, 5), which showed that PMS2 is a latent endonuclease that introduces additional nicks into the discontinuous DNA strand of nicked heteroduplex substrates. This activity is dependent on the integrity of a highly conserved metal-binding motif found in many MutL homologs, including MLH3. MutLα appears to play an essential role in 3′-directed MMR, where the bias for incision on the distal side of the mismatch results in a 5′ entry site for MutSα-activated Exo1. For 5′-directed MMR, however, several studies in both the reconstituted human MMR system and MutLα-deficient cells have shown that MutLα is not essential, and that a purified system consisting of MutSα, Exo1, and RPA is sufficient to support 5′-directed MMR (6, 7). Studies in yeast have further delineated roles of the PMS2 endonuclease activity in DNA repair, recombination, and the DNA damage response (5,8,9).Pms2 −/− mice (10) showed an increase in base substitution and insertion/deletion mutation frequencies at both a reporter locus and microsatellite sequences, with a higher proportion of frameshift mutations compared with other MMR knockout models, such as...

show abstract

Section: (F) Thementioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

Oers

Roa

Werling

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…The number of SNPs constitute a major point of difference between any two closely related polymorphic regions [24,25] sets and see [36,37]). …”

Section: Changing Views On the Origin Of Snpsmentioning

confidence: 99%

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

et al. 2011

Self Cite

View full text Add to dashboard Cite

how mutations in newly synthesized RNA might be copied back to DNA thus accounting for some of the genome-wide strand biases (e.g. the A-to-G vs T-to-C component of the strand biased spectrum). We hypothesize that the genesis of PFBs and extended AHs occurs during mutagenic episodes in evolution (e.g. retroviral infections) and that many of the critical DNA sequence diversifying events occur first at the RNA level e.g. recombination between RNA strings resulting in tandem and dispersed RNA duplications (retroduplications), RNA mutations via adenosine-to-inosine pre-mRNA editing events as well as error prone RNA synthesis. These are then copied back into DNA by a cellular reverse transcription (RT) process (also likely to be error-prone) we have called "RTmediated long DNA conversion" (RT-LDC). Finally we suggest that all these activities and others can be envisaged as being brought physically under the umbrella of special sites in the nucleus involved in transcription known as "Transcription Factories" (TF).

show abstract

Inosine‐specific ribonuclease activity of natural variants of human endonuclease V

et al. 2016

View full text Add to dashboard Cite

Adenine bases in DNA, RNA, and nucleotides are deaminated during normal metabolism via hydrolytic and nitrosative reactions. In RNA, the deaminated product inosine is resolved by human endonuclease V, and mice deficient in this enzyme are cancer-prone. We have now produced, purified, and characterized naturally occurring variants of human endonuclease V (V29I, R112Q, K114R, H141Y, and D201N). We found that H141Y, but not other variants, is catalytically impaired, suggesting that individuals homozygous for H141Y may be predisposed to disease.

show abstract

Mechanism of somatic hypermutation: Critical analysis of strand biased mutation signatures at A:T and G:C base pairs

Cited by 42 publications

References 120 publications

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

PMS2 endonuclease activity has distinct biological functions and is essential for genome maintenance

Genesis of ancestral haplotypes: RNA modifications and reverse transcription–mediated polymorphisms

Inosine‐specific ribonuclease activity of natural variants of human endonuclease V

Contact Info

Product

Resources

About