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11 MutSa and UNG2 do not Compete During SHM: Cell Cycle and Error-Free Repair

11 MutSa and UNG2 do not Compete During SHM: Cell Cycle and Error-Free Repair

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Error-Prone and Error-Free Resolution of AID Lesions in SHM


UNG2-dependent mutagenesis, a finding consistent with the noncompetitive model of SHM. In line with this model, MSH2 seems

incapable of removing uracils usually processed by UNG2, as revealed

by the selective and compensatory increase of G/C transitions as a

consequence of direct replication over the U. In summary, these data

indicate that uracils normally recognized and processed by UNG2 remain

refractory to MSH2-dependent SHM in UNG2-deficient B cells.

The reverse situation, whether UNG2 is capable of removing uracils

normally processed by MSH2, was addressed by comparing the efficacy

in the generation of G/C transversions between WT and MSH2-deficient

B cells. If UNG2 mutagenesis would compete with MSH2, one expects

G/C transversions to increase in the absence of MSH2. However, as

mentioned previously, the lack of mismatch recognition results in a twofold decrease in the frequency of these mutations. Furthermore, the lack

of mismatch recognition does not change the efficacy in generating G/C

transitions, suggesting that prior to replication, U usually processed by

MSH2 are now repaired by BER. These data further support the noncompetitive model. A model of how the separation of MSH2- and

UNG2-dependent mutation can be achieved was proposed recently by

J.C. Weill and C.A. Reynaud (Weill and Reynaud, 2008). In this model

uracils which may arise as a consequence of processive AID activity

(Storb et al., 2009; Pham et al., 2003) are introduced on both strands at

distinct phases of the cell cycle (Aoufouchi et al., 2008). U introduced

during the S phase can directly act as template T during replication to

generate G/C transitions or be converted to an AP site by UNG2. If not

repaired, the AP site causes replicative polymerase to stall and activate a

TLS polymerase to initiate the generation of G/C transversions (and

possibly transitions) and some A/T mutations. Uracils generated outside

the S-phase would be recognized as a U:G mismatch by MSH2-MSH6,

resulting in mutations at template A/T. In support of this model, UNG is

strongly upregulated in the transition from the G1 to S phase (Hagen

et al., 2008). In, addition, Polη is recruited upon DNA damage in cells

arrested in G1 (Soria et al., 2009). Although MMR normally is postreplicative, components such as MutSα and Exo1 may function outside

of the S phase to support SHM.


DNA Deamination and the Immune System

6.12 Aberrant Targeting of AID and Error-Free Repair of

AID-Induced Uracils

It has been known for over a decade, that non-Ig genes can be mutated

during SHM. Memory B cells isolated from human peripheral blood

were found to have mutations in the BCL6 gene (Shen et al., 1998). The

BCL6 gene was sequenced in the first intron from 0.64 to 1.43kb from

the start of transcription and the peak of mutations was found in the first

half of this region. No mutations were seen further 3′ between 2.4 to

3.2kb from the promoter. The mutation frequencies in the hypermutable

region were 2x10-3 to 7x10-4. In one donor, where the mutation

frequency of BCL6 was 2x10-3, IgH genes had mutations at a 5x10-2

frequency, in the normal range of IgH mutations in humans. Thus,

BCL6 mutations are at a one to two orders lower frequency than Ig gene

mutations, but the pattern of mutations is the same as that of Ig genes.

No BCL6 mutations were seen in resting B cells from the same donors.

These findings were confirmed in tonsillar germinal center B cells and B

cell lymphomas (Pasqualucci et al., 1998; Peng et al., 1999).

Mutations were also found in other non-Ig genes. About 15% of

germinal center and memory, but not naïve B cells of normal human

donors, were found to have mutations in the CD95 gene (Muschen et al.,

2000). Also, the Ig-alpha and Ig-beta genes were found mutated in

malignant and normal human B cells (Gordon et al., 2003). Mutations

were also found in four proto-oncogenes in diffuse large-cell lymphomas

that express AID: PIM1, MYC, RhoH/TTF and PAX5 (Pasqualucci

et al., 2001). Initially, these genes appeared not mutated in normal human

germinal center B cells or in other germinal-center-derived lymphomas.

However, an extended analysis of these genes in germinal center B cells

of wild-type mice revealed that these highly expressed genes do mutate

in an AID-dependent manner, albeit at a low frequency (Liu et al., 2008).

It appeared thus, that these non-Ig genes are targeted by AID and may

have cis-elements that can attract AID. Furthermore, these data indicate

that certain germinal center-derived lymphomas are prone to accumulate

mutations in non-Ig genes.

Error-Prone and Error-Free Resolution of AID Lesions in SHM


Other non-Ig genes were found not to be mutated significantly in

normal human memory B cells: c-MYC was mutated at the very low

frequency of ~1 x10-4: no mutations were found in ribosomal small

subunit protein S14, α-fetoprotein, TBP and survivin (Shen et al., 1998;

Shen et al., 2000). However, many of the expressed non-Ig genes were

mutated in germinal center B cells of Msh2/Ung double-deficient mice

(Liu et al., 2008). The same genes were mutated at 0.6 to 17.4 lower

frequencies in wild-type mice. The list included the c-Myc gene found

in human memory B cells to be mutated at a frequency of ~1 x10-4 (Shen

et al., 1998). Myc was mutated in the double-knockout mice at about a

10x higher frequency of ~1 x10-3 (Liu et al., 2008). It was concluded

that these non-Ig genes suffered C to U deaminations by AID but that the

uracils were repaired error-free and the authors considered that there

were different mechanisms of dealing with AID-induced uracils: errorprone in Ig and BCL6 genes, but error-free in other genes.

This idea assumes that uracils in Ig genes are not repaired in an errorfree fashion. However, a recent analysis of MMR/BER double-deficient

mice showed that AID-induced uracils are repaired efficiently in Ig genes

(Storb et al., 2009). The data indicated that 39 to 47% of the mutations

in Ig genes of the double-knockout mice were repaired error-free in wildtype mice. This percentage is likely to be an underestimate, as the

number of G/C transitions found in Ung/MMR-/- mice only arose from

uracils that were not processed by Ung; additionally, other redundant

uracil glycosylases such as Smug1 (Di Noia et al., 2006) – see previous

sections in this chapter – may compete for repair of such lesions. The

actual number of G/C mutations is likely to be higher if the other

uracil glycosylases were also absent. Therefore, the proportion of

uracils repaired error-free (39–47%) in Ig genes is likely to be an


Assuming that error-free repair plays an equally major role in

curtailing mutations in Ig genes as well as non-Ig genes, one wonders

whether or not there is a special mechanism active during SHM to submit

any gene to error-prone repair. Most of the error-free repair of uracils in

Ig genes is apparently due to Ung rather than MMR (Storb et al., 2009).

Possibly, there is a random chance for error-free repair occurring before


DNA Deamination and the Immune System

error-prone mechanisms can act, as discussed in other sections of this

chapter. Ung is also involved in error-prone repair, since in MMRdeficient mice, transversions at G/C and mutations at A/T still occur

(Rada et al., 1998; Frey et al., 1998). Thus, it is possible that Ung’s

activity is neutral in outcome. Clearly, Ig genes are targeted at much

higher frequencies than any non-Ig genes. This is presumably due to the

combination of high transcription rates and a high frequency and intragenic location of a cis-acting element, CAGGTG, which has been shown

to be sufficient to attract AID to a target gene (Tanaka et al., 2010).

With lower transcription rates and fewer CAGGTG elements, non-Ig

genes acquire many fewer AID-induced uracils than Ig genes. Perhaps

the uracil load is generally low enough in non-Ig genes to ensure that

most are repaired error-free. Ig genes, on the other hand, may become

overloaded with uracils, so that abasic sites created by Ung (and perhaps

other uracil glycosylases: see previous sections of this chapter) lead to

the recruitment of lesion bypass, error-prone polymerases and, therefore,

stable mutations. This scenario has some support in the finding that

over-expression of AID causes SHM in various genes and mutations

even in non-germinal center B cells and non-B cells. AID transfected

into B cell hybridomas caused mutation of the endogenous VH genes

(Martin et al., 2002). Transgenic AID in Chinese hamster ovary cells

caused mutations in the AID transgene itself (Martin and Scharff, 2002).

Transgenic AID also caused mutations in an artificial GFP substrate in

NIH 3T3 fibroblasts (Yoshikawa et al., 2002). Thus, AID does not

appear to require germinal center B cell-specific co-factors to cause

mutations when it is over-expressed. However, the marked shift of the

mutation signature towards G/C transition mutations suggests that these

mutations do not require error-prone repair and simply arise as a

consequence of replication across U. The balance between error-free and

error-prone repair, as well as the signature of SHM is likely to depend on

several factors, i.e. the number of cytidine deaminations, the cell-cycle

stage when lesions are introduced, the sequence context, the (in)activity

of DNA repair, DNA damage tolerance and DNA damage response


Error-Prone and Error-Free Resolution of AID Lesions in SHM


6.13 Acknowledgements

The work described in this chapter was supported by The Netherlands

Organisation for Scientific Research (VIDI program NWO 917.56.328 to

H.J.), SFN (SFN 2.129 to H.J) the Dutch Cancer Society (KWF project

NKI 2008-4112 to H.J.) and NIH grants (AI047380 and AI081167 to


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11 MutSa and UNG2 do not Compete During SHM: Cell Cycle and Error-Free Repair

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