APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination

Guikema, Jeroen E. J.; Linehan, Erin K.; Tsuchimoto, Daisuke; Nakabeppu, Yusaku; Stavnezer, Janet; Schrader, Carol E.

doi:10.1084/jem.20071289120507c

Cited by 39 publications

(54 citation statements)

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“…These uracils serve as a critical launching point for the mutagenic and recombination events that take place during antibody diversification, and are excised by uracil-DNA glycosylase (UNG), which generates an abasic site product. Guikema et al, using APE1 haploinsufficient mice (APE1 + / -), reported reduced CSR in the S region of splenic B cells due to a decrease in DNA doublestrand break formation, consistent with a role for APE1 in the AP site cleavage step (66). The authors also found that CSR was reduced in APE2-deficient mice, implicating both exonuclease III-like proteins in the process of isotype switching and suggesting a possible specialized DNA processing function for APE2 in activated B cells.…”

Section: Participation In Specific Cellular Processesmentioning

confidence: 92%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

224

221

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Significance: Human apurinic/apyrimidinic endonuclease 1 (APE1, also known as REF-1) was isolated based on its ability to cleave at AP sites in DNA or activate the DNA binding activity of certain transcription factors. We review herein topics related to this multi-functional DNA repair and stress-response protein. Recent Advances: APE1 displays homology to Escherichia coli exonuclease III and is a member of the divalent metal-dependent a/b fold-containing phosphoesterase superfamily of enzymes. APE1 has acquired distinct active site and loop elements that dictate substrate selectivity, and a unique N-terminus which at minimum imparts nuclear targeting and interaction specificity. Additional activities ascribed to APE1 include 3¢-5¢ exonuclease, 3¢-repair diesterase, nucleotide incision repair, damaged or site-specific RNA cleavage, and multiple transcription regulatory roles. Critical Issues: APE1 is essential for mouse embryogenesis and contributes to cell viability in a genetic background-dependent manner. Haploinsufficient APE1 +/ -mice exhibit reduced survival, increased cancer formation, and cellular/tissue hyper-sensitivity to oxidative stress, supporting the notion that impaired APE1 function associates with disease susceptibility. Although abnormal APE1 expression/localization has been seen in cancer and neuropathologies, and impaired-function variants have been described, a causal link between an APE1 defect and human disease remains elusive. Future Directions: Ongoing efforts aim at delineating the biological role(s) of the different APE1 activities, as well as the regulatory mechanisms for its intra-cellular distribution and participation in diverse molecular pathways. The determination of whether APE1 defects contribute to human disease, particularly pathologies that involve oxidative stress, and whether APE1 small-molecule regulators have clinical utility, is central to future investigations. Antioxid. Redox Signal. 20,

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Section: Participation In Specific Cellular Processesmentioning

confidence: 92%

Human Apurinic/Apyrimidinic Endonuclease 1

2014

Antioxidants & Redox Signaling

224

221

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“…Previously we showed that APE1 is constitutively expressed and APE2 is inducibly expressed in mouse splenic B cells induced to undergo CSR in culture (26). Because these cultured B cells do not undergo SHM, which occurs only in vivo in GCs, we compared the expression of APE1 and APE2 in total cell extracts of GC and non-GC cells from PPs.…”

Section: Ape1mentioning

confidence: 99%

“…GC B cells were sorted from 7-wk to 9-mo-old unimmunized mice, and age did not appear to affect the results. APE1-heterozygous mice were analyzed because apex1 −/− mice die during early embryogenesis, and APE1 heterozygotes are haploinsufficient and have DNA repair and CSR deficiencies (26,37,38). Table 1 presents the mutation frequency and base specificity data for the WT and APE-deficient mice.…”

Section: Ape1mentioning

confidence: 99%

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Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation

Stavnezer

Linehan

Thompson

et al. 2014

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

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Somatic hypermutation (SHM) of antibody variable region genes is initiated in germinal center B cells during an immune response by activation-induced cytidine deaminase (AID), which converts cytosines to uracils. During accurate repair in nonmutating cells, uracil is excised by uracil DNA glycosylase (UNG), leaving abasic sites that are incised by AP endonuclease (APE) to create single-strand breaks, and the correct nucleotide is reinserted by DNA polymerase β. During SHM, for unknown reasons, repair is error prone. There are two APE homologs in mammals and, surprisingly, APE1, in contrast to its high expression in both resting and in vitro-activated splenic B cells, is expressed at very low levels in mouse germinal center B cells where SHM occurs, and APE1 haploinsufficiency has very little effect on SHM. In contrast, the less efficient homolog, APE2, is highly expressed and contributes not only to the frequency of mutations, but also to the generation of mutations at A:T base pair (bp), insertions, and deletions. In the absence of both UNG and APE2, mutations at A:T bp are dramatically reduced. Single-strand breaks generated by APE2 could provide entry points for exonuclease recruited by the mismatch repair proteins Msh2-Msh6, and the known association of APE2 with proliferating cell nuclear antigen could recruit translesion polymerases to create mutations at AIDinduced lesions and also at A:T bp. Our data provide new insight into error-prone repair of AID-induced lesions, which we propose is facilitated by down-regulation of APE1 and up-regulation of APE2 expression in germinal center B cells. D uring humoral immune responses, the recombined antibody variable [V(D)J] region genes undergo somatic hypermutation (SHM), which, after selection, greatly increases the affinity of antibodies for the activating antigen. This process occurs in germinal centers (GCs) in the spleen, lymph nodes, and Peyer's patches (PPs) and entirely depends on activation-induced cytidine deaminase (AID) (1, 2). AID initiates SHM by deamination of cytidine nucleotides in the variable region of antibody genes, converting the cytosine (dC) to uracil (dU) (1, 3, 4). Some AIDinduced dUs are excised by the ubiquitous enzyme uracil DNA glycosylase (UNG), resulting in abasic (AP) sites that can be recognized by apurinic/apyrimidinic endonuclease (APE) (4, 5). APE cleaves the DNA backbone at AP sites to form a singlestrand break (SSB) with a 3′ OH that can be extended by DNA polymerase (Pol) to replace the excised nucleotide (6). In most cells, DNA Pol β performs this extension with high fidelity, reinserting dC across from the template dG. In contrast, GC B cells undergoing SHM are rapidly proliferating, and some of the dUs are replicated over before they can be excised and are read as dT by replicative polymerases, resulting in dC to dT transition mutations. Unrepaired AP sites encountering replication lead to the nontemplated addition of any base opposite the site, causing transition and transversion mutations. However, it is not clear why dU...

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“…The main route for processing AID-induced lesions involves uracil excision through several pathways, primarily the pathway involving uracil-DNA glycosylase (UNG2) (4,5). Abasic sites are further processed to generate DNA double-strand breaks (DSBs), which are obligate intermediates in CSR (6,7). The DSBs activate damage response proteins, such as PI3-like protein kinase ataxia-telangiectasia mutated, the phosphorylated histone variant H2AX, the MRN complex (MRE11, RAD50, and NBS1), MDC1, and 53BP1, all of which are known to play roles in CSR in promoting appropriate repair and efficient long-range, region-specific recombination (8)(9)(10)(11)(12)(13)(14).…”

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confidence: 99%

Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair

Kracker

Imai

Gardès

et al. 2010

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

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Ig class-switch recombination (CSR) is a region-specific process that exchanges the constant Ig heavy-chain region and thus modifies an antibody's effector function. DNA lesions in switch (S) regions are induced by activation-induced cytidine deaminase (AID) and uracil-DNA glycosylase 2 (UNG2), subsequently processed to DNA breaks, and resolved by either the classical nonhomologous endjoining pathway or the alternative end-joining pathway (XRCC4/ DNA ligase 4-and/or Ku70/Ku80-independent and prone to increased microhomology usage). We examined whether the induction of DNA lesions influences DNA end-joining during CSR by analyzing Sμ-Sα recombination junctions in various human Ig CSR defects of DNA lesion induction. We observed a progressive trend toward the usage of microhomology in Sμ-Sα recombination junctions from AID-heterozygous to AID-autosomal dominant to UNG2-deficient B lymphocytes. We thus hypothesize that impaired induction of DNA lesions in S regions during CSR leads to unusual end-processing of the DNA breaks, resulting in microhomology-mediated end-joining, which could be an indication for preferential processing by alternative end-joining rather than by classical nonhomologous end-joining.antibody maturation | switch junction | DNA repair D uring immune responses, mature B cells diversify their Ig genes through class-switch recombination (CSR) and somatic hypermutation (SHM). The latter mechanism introduces nontemplated point mutations in the variable region of Ig genes and thereby enables the selection of antibodies with increased affinity for the antigen. CSR modulates antibody effector function by replacing one constant region with another in a deletionmediated recombination process, while retaining the binding specificity (variable region) of the B-cell receptor. Both processes are initiated by the enzyme activation-induced cytidine deaminase (AID), which deaminates cytosine to produce U:G mismatches in target DNA (1-3). GC-rich regions, so-called "switch" (S) regions, present in front of each constant region and of varying lengths, are the target DNAs for AID during CSR. The main route for processing AID-induced lesions involves uracil excision through several pathways, primarily the pathway involving uracil-DNA glycosylase (UNG2) (4, 5). Abasic sites are further processed to generate DNA double-strand breaks (DSBs), which are obligate intermediates in CSR (6, 7). The DSBs activate damage response proteins, such as PI3-like protein kinase ataxia-telangiectasia mutated, the phosphorylated histone variant H2AX, the MRN complex (MRE11, RAD50, and NBS1), MDC1, and 53BP1, all of which are known to play roles in CSR in promoting appropriate repair and efficient long-range, region-specific recombination (8)(9)(10)(11)(12)(13)(14). In CSR, the resolution step is normally mediated by the classical nonhomologous end-joining pathway (c-NHEJ); however, recent reports strongly suggest that resolution also can be mediated (albeit at a lower frequency) by Ku 70-, Ku 80-, and/or XRCC4/DNA ligase 4-independen...

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APE1- and APE2-dependent DNA breaks in immunoglobulin class switch recombination

Cited by 39 publications

References 0 publications

Human Apurinic/Apyrimidinic Endonuclease 1

Human Apurinic/Apyrimidinic Endonuclease 1

Differential expression of APE1 and APE2 in germinal centers promotes error-prone repair and A:T mutations during somatic hypermutation

Impaired induction of DNA lesions during immunoglobulin class-switch recombination in humans influences end-joining repair

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