Replication protein A interacts with AID to promote deamination of somatic hypermutation targets

Chaudhuri, Jayanta; Khuong, Chan; Alt, Frederick W.

doi:10.1038/nature02821

Cited by 348 publications

(364 citation statements)

References 50 publications

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“…6 and 7), points to a requirement for a GC-specific signal for the onset of SHM but not CSR. Such a scenario is consistent with the recent data implying that the association of AID with replication protein A is required for SHM but not CSR (38).…”

Section: Discussionsupporting

confidence: 92%

Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen

Phan

Gardam

Basten

et al. 2005

The Journal of Immunology

104

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The early responses of follicular (Fo) and marginal zone (MZ) B cells to T cell-dependent Ag were compared using anti-hen egg lysozyme (HEL+) B cells capable of class switch recombination and somatic hypermutation (SHM). Purified CD21/35intCD23high Fo and CD21/35highCD23low MZ splenic B cells from SWHEL Ig-transgenic mice were transferred into wild-type recipients and challenged with HEL-sheep RBC. Responding HEL+ B cells from both populations switched efficiently to IgG1, generated syndecan-1+ Ab-secreting cells, and exhibited equivalent rates of proliferation. However, the expansion of HEL+ MZ B cells lagged significantly behind that of HEL+ Fo B cells due to less efficient homing to the outer periarteriolar lymphatic sheath and reduced recruitment into the proliferative response. Despite the equivalent rates of class switch recombination, the onset of SHM was delayed in the MZ subset, indicating that these two activation-induced cytidine deaminase-dependent events are uncoupled in the early response of MZ B cells. Migration of HEL+ B cells into germinal centers coincided with the onset of SHM, occurring more rapidly with Fo vs MZ responders. These results are consistent with the concept that Fo and MZ B cells have evolved to specialize in T cell-dependent and T-independent responses respectively.

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Section: Discussionsupporting

confidence: 92%

Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen

Phan

Gardam

Basten

et al. 2005

The Journal of Immunology

104

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“…RPA acts in homologous recombination (HR) to stimulate DNA annealing using physical interactions with Rad52 (4 -7) and in HR-mediated DNA repair, probably employing specific interactions with BRCA2 (8,9). RPA is a required factor in both the nucleotide excision (10,11) and mismatch repair pathways (12,13) and in somatic hypermutation (14). Because of these many roles, it is of significant interest to understand the mechanisms that regulate RPA activity.…”

mentioning

confidence: 99%

Sequential and Synergistic Modification of Human RPA Stimulates Chromosomal DNA Repair

Anantha

Vassin

Borowiec

2007

Journal of Biological Chemistry

150

211

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The activity of human replication protein A (RPA) in DNA replication and repair is regulated by phosphorylation of the middle RPA2 subunit. It has previously been shown that up to nine different N-terminal residues are modified in vivo and in response to genotoxic stress. Using a novel antibody against phospho-Ser 29 , a moiety formed by cyclin-Cdk, we observed that RPA2 was phosphorylated during mitosis in nonstressed cells. Robust phosphorylation of Ser 29 was also seen in interphase cells following treatment with the DNA-damaging agent camptothecin, a rare example of stress stimulating the modification of a repair factor by cyclin-Cdk. RPA2 phosphorylation is regulated both in cis and trans. Cis-phosphorylation follows a preferred pathway. (That is, the initial modification of Ser 33 by ATR stimulates subsequent phosphorylation of Cdk sites Ser 23 and Ser 29 ). These events then facilitate modification of Thr 21 and extreme N-terminal sites Ser 4 and Ser 8 , probably by DNA-PK. Our data also indicate that the phosphorylation of one RPA molecule can influence the phosphorylation of other RPA molecules in trans. Cells in which endogenous RPA2 was "replaced" with a double S23A/S29A-RPA2 mutant were seen to have an abnormal cell cycle distribution both in normal and in stressed cells. Such cells also showed aberrant DNA damage-dependent RPA foci and had persistent staining of ␥H2AX following DNA damage. Our data indicate that RPA phosphorylation facilitates chromosomal DNA repair. We postulate that the RPA phosphorylation pattern provides a means to regulate the DNA repair pathway utilized.Replication protein A (RPA) 2 is a heterotrimeric singlestranded DNA-binding factor that is critical for the "three Rs" of eukaryotic DNA enzymology: DNA replication, DNA recombination, and DNA repair (1, 2). For DNA replication, the study of cellular and viral model systems demonstrates that RPA is needed both for origin denaturation and replication elongation, in the latter case to facilitate the switch from DNA polymerase ␣ to DNA polymerase ␦ during Okazaki fragment synthesis (3). RPA acts in homologous recombination (HR) to stimulate DNA annealing using physical interactions with Rad52 (4 -7) and in HR-mediated DNA repair, probably employing specific interactions with BRCA2 (8, 9). RPA is a required factor in both the nucleotide excision (10, 11) and mismatch repair pathways (12, 13) and in somatic hypermutation (14). Because of these many roles, it is of significant interest to understand the mechanisms that regulate RPA activity.Of the ϳ70-kDa (RPA1), 30-kDa (RPA2), and 14-kDa (RPA3) subunits, human RPA is subject to extensive phosphorylation on RPA2 (2) and at one RPA1 site (15). The N-terminal 33 residues of RPA2 undergo both cell cycle-and stress-dependent phosphorylation on approximately nine sites (Fig. 1A), which are thought to exist in an unstructured conformation (16,17). Ser 23 and Ser 29 are constitutively modified during mitosis by cyclin B-Cdk1 (18, 19) and have been suggested to be partially modified beginni...

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“…Such R loops are effective AID substrates in vitro (20,21). Second, in activated B cells, AID is phosphorylated, allowing it to interact with replication protein A (RPA) (22). In vitro, AID͞RPA complex preferentially binds to and deaminates sequences, such as variable regions and S regions, which are rich in AGCT and related motifs.…”

mentioning

confidence: 99%

Influence of switch region length on immunoglobulin class switch recombination

Zarrin

Tian

Wang

et al. 2005

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

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The class and effector functions of antibodies are modulated through the process of Ig heavy chain class switch recombination (CSR). CSR occurs between switch (S) regions that lie upstream of the various Ig heavy chain constant region exons. Molecular analyses of S-region functions have been hampered by their large size and repetitive nature. To test potential relationships between S-region size and efficiency of CSR, we generated normal B lymphocytes in which the 12-kb S region flanking the C␥1 exons (S␥1) was replaced with synthetic or endogenous S regions of various lengths. Replacement of S␥1 with 1-and 2-kb synthetic sequences representing the S␥1 core repeats or a 4-kb portion of the core endogenous S␥1 region supported CSR frequencies that directly correlated with S-region length. These findings indicate that Sregion size is an important factor in determining endogenous CSR efficiency. Moreover, these results also will allow the development of a systematic system to test the function of various S-region motifs by replacing endogenous S regions with synthetic S regions controlled for size effects.IgH switch region ͉ activation-induced deaminase ͉ synthetic switch region ͉ IgG1

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Replication protein A interacts with AID to promote deamination of somatic hypermutation targets

Cited by 348 publications

References 50 publications

Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen

Altered Migration, Recruitment, and Somatic Hypermutation in the Early Response of Marginal Zone B Cells to T Cell-Dependent Antigen

Sequential and Synergistic Modification of Human RPA Stimulates Chromosomal DNA Repair

Influence of switch region length on immunoglobulin class switch recombination

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