Balancing AID and DNA repair during somatic hypermutation

Liu, Man; Schatz, David G.

doi:10.1016/j.it.2009.01.007

Cited by 179 publications

(162 citation statements)

References 63 publications

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“…However, there is little evidence for cofactors that restrict the activity of AID specifically to the Ig genes, although Liu and Schatz have proposed that nonIg loci are protected from AID-induced SHM by high-fidelity DNA repair (46). The present study showed that constitutive expression of AID was not sufficient for SHM induction in DT40-ASF cells, although the amount of AID was enough to cause translocations when SRSF1 was depleted.…”

Section: Srsf1-3 Collaborates With Aid To Inhibit Splicing Of Ig Trancontrasting

confidence: 57%

Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1

Kanehiro

Todo

Negishi

et al. 2012

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

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Somatic hypermutation (SHM) of Ig variable region (IgV) genes requires both IgV transcription and the enzyme activation-induced cytidine deaminase (AID). Identification of a cofactor responsible for the fact that IgV genes are much more sensitive to AID-induced mutagenesis than other genes is a key question in immunology. Here, we describe an essential role for a splice isoform of the prototypical serine/arginine-rich (SR) protein SRSF1, termed SRSF1-3, in AID-induced SHM in a DT40 chicken B-cell line. Unexpectedly, we found that SHM does not occur in a DT40 line lacking SRSF1-3 (DT40-ASF), although it is readily detectable in parental DT40 cells. Strikingly, overexpression of AID in DT40-ASF cells led to a large increase in nonspecific (off-target) mutations. In contrast, introduction of SRSF1-3, but not SRSF1, into these cells specifically restored SHM without increasing off-target mutations. Furthermore, we found that SRSF1-3 binds preferentially to the IgV gene and inhibits processing of the Ig transcript, providing a mechanism by which SRSF1-3 makes the IgV gene available for AID-dependent SHM. SRSF1 not only acts as an essential splicing factor but also regulates diverse aspects of mRNA metabolism and maintains genome stability. Our findings, thus, define an unexpected and important role for SRSF1, particularly for its splice variant, in enabling AID to function specifically on its natural substrate during SHM.gene conversion | genomic instability S omatic hypermutation (SHM) and class switch recombination (CSR) of Ig genes are key processes needed to generate functional antibodies (Abs) with high affinity in humoral immune responses. Activation-induced cytidine deaminase (AID) is crucial for both SHM and CSR (1, 2), which are initiated by AIDcatalyzed deamination of dC to dU in the variable (V) region and the switch (S) region DNA strands, respectively (3, 4). However, AID has been recently shown to bind numerous chromosomal locations genome-wide and to mutate non-Ig genes, although the mutation frequency of non-Ig genes is much lower than that of the Ig genes (5, 6). It has been proposed that specific cofactors interact with AID and regulate its activity in a target-specific manner (7). AID has been reported to associate with several proteins including RPA (8, 9), protein kinase A (10), RNA polymerase II (Pol II) (11), DNA-PKcs (12), MDM2 (13), Spt6 (14), 14-3-3 (15), Spt5 (16), CTNNBL1 (17), PTBP2 (18), RNA exosome subunits (19), KAP1 (20), and HP1 (20). However, these investigations were mostly focused on CSR, and, thus, the identified factors themselves are not sufficient to explain how AID activity is specifically targeted to the IgV genes during SHM.SHM occurs in IgV region exons starting 100-200 bp downstream of the promoter and extending over 1-2 kb, preferentially targeting WRC/GYW hotspot motifs (3, 4). Importantly, the activity of the SHM machinery strictly depends on transcription of the IgV genes (21, 22). In vitro experiments have shown that replication protein A (RPA) binds to and stabilize...

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Section: Srsf1-3 Collaborates With Aid To Inhibit Splicing Of Ig Trancontrasting

confidence: 57%

Activation-induced cytidine deaminase (AID)-dependent somatic hypermutation requires a splice isoform of the serine/arginine-rich (SR) protein SRSF1

Kanehiro

Todo

Negishi

et al. 2012

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

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“…It was shown that C:G>T:A transitions at XpCpG trinucleotides were especially prominent in many cancer types 27,44 . Among the C:G>T:A transitions, the footprint of AID is characterized by C:G>T:A alterations that occur in GpCpX or ApCpX sequences 22,28,29,[45][46][47] . In the current study, previously established mouse models with inflammation-associated gastric carcinogenesis [50][51][52] .…”

Section: Discussionmentioning

confidence: 99%

Accumulation of Somatic Mutations in TP53 in Gastric Epithelium With Helicobacter pylori Infection

et al. 2014

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“…According to the recent studies, the balance between errorprone repair (EPR) and high-fidelity repair (HFR) determines the outcome of AID-generated uracils, that is, accumulation or elimination of mutations. 29 It is tempting to speculate that the frequencies of uracils generated by AID are not different between the myeloid-and lymphoid-lineage, but that HFR overcomes EPR in the myeloid-lineage. In any case, solving the riddle of how AID induces leukemia/lymphoma in a celllineage-dependent manner will help understand AID functions.…”

Section: Discussionmentioning

confidence: 99%