Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1

Bothmer, Anne; Robbiani, Davide F.; Virgilio, Michela Di; Bunting, Samuel F.; Klein, I.; Feldhahn, Niklas; Barlow, Jacqueline H.; Chen, Hua Tang; Bosque, David; Callén, Elsa; Nussenzweig, André; Nussenzweig, Michel C.

doi:10.1016/j.molcel.2011.03.019

Cited by 213 publications

(299 citation statements)

References 55 publications

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“…These results were not due to transfection efficiency since SIRT7‐KD cells were equally transfected as compared with control cells (Appendix Fig S6C and D). In addition, we evaluated immunoglobulin class switching recombination, a process that relies on end joining, and specifically 53BP1 activity (Bothmer et al , 2011). The switching from IgM to IgG1 and IgG3 was measured by FACS in splenic B cells.…”

Section: Resultsmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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Section: Resultsmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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“…Taken together, these data demonstrate that 53BP1 deficiency results in a loss of cCSR with a concomitant increase in AID-dependent S μ -σ δ CSR at defined anatomic sites that more than compensates for the loss of cCSR. In the absence of 53BP1, AID-mediated DNA DSBs at the Igh locus are repaired by ATM-dependent alternative nonhomologous end-joining (A-NHEJ; suppressed by canonical NHEJ) in the G1 phase or by homologous recombination (HR) in the S-G2/M phase of the cell cycle (10)(11)(12)(13). Extensive DNA template resection in HR inhibits ATM activity and reduces the formation of chromosomal translocations via A-NHEJ (14).…”

Section: Significancementioning

confidence: 99%

IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

Choi

Wang

Zhang

et al. 2017

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

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Class-switch recombination (CSR) alters the Ig isotype to diversify antibody effector functions. IgD CSR is a rare event, and its regulation is poorly understood. We report that deficiency of 53BP1, a DNA damage-response protein, caused age-dependent overproduction of secreted IgD resulting from increased IgD CSR exclusively within B cells of mucosa-associated lymphoid tissues. IgD overproduction was dependent on activation-induced cytidine deaminase, hematopoietic MyD88 expression, and an intact microbiome, against which circulating IgD, but not IgM, was reactive. IgD CSR occurred via both alternative nonhomologous end-joining and homologous recombination pathways. Microbiota-dependent IgD CSR also was detected in nasal-associated lymphoid tissue of WT mice. These results identify a pathway, present in WT mice and hyperactivated in 53BP1-deficient mice, by which microbiota signal via Toll-like receptors to elicit IgD CSR.

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“…The 53BP1 has a major role in NHEJ repair. 39 RNF8 also facilitates NHEJ repair by regulating the abundance of the NHEJ repair protein KU80 at sites of DNA damage. 40 We examined NHEJ repair by using a well-characterized plasmid-based end-joining assay.…”

Section: Bzlf1 Impairs Dsb Repair and Activates Atmdependent Signalinmentioning

confidence: 99%

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

Yang

Deng

Hau

et al. 2015

Laboratory Investigation

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Epstein-Barr virus (EBV) infection is closely associated with several human malignancies including nasopharyngeal carcinoma (NPC). The EBV immediate-early protein BZLF1 is the key mediator that switches EBV infection from latent to lytic forms. The lytic form of EBV infection has been implicated in human carcinogenesis but its molecular mechanisms remain unclear. BZLF1 has been shown to be a binding partner of several DNA damage response (DDR) proteins. Its functions in host DDR remain unknown. Thus, we explore the effects of BZLF1 on cellular response to DNA damage in NPC cells. We found that expression of BZLF1 impaired the binding between RNF8 and MDC1 (mediator of DNA damage checkpoint 1), which in turn interfered with the localization of RNF8 and 53BP1 to the DNA damage sites. The RNF8-53BP1 pathway is important for repair of DNA double-strand breaks and DNA damage-induced G2/M checkpoint activation. Our results showed that, by impairing DNA damage repair as well as abrogating G2/M checkpoint, BZLF1 induced genomic instability and rendered cells more sensitive to ionizing radiation. Moreover, the blockage of 53BP1 and RNF8 foci formation was recapitulated in EBV-infected cells. Taken together, our study raises the possibility that, by causing mis-localization of important DDR proteins, BZLF1 may function as a link between lytic EBV infection and impaired DNA damage repair, thus contributing to the carcinogenesis of EBV-associated human epithelial malignancies. Epstein-Barr virus (EBV) is a gamma herpesvirus and infection with EBV is associated with a variety of epithelial and B-cell cancers. 1,2 EBV has a biphasic life cycle consisting of latent and lytic stages. The switch from latent to lytic infection is triggered by the EBV immediate-early transcription factor, BZLF1 (ZEBRA, Zta, Z, EB1). 3,4 A number of reports have demonstrated that lytic EBV activation is intimately linked to the pathogenesis of EBV-induced malignancies including the development of NPC. [5][6][7][8] The mammalian DNA damage response (DDR) network has pivotal roles in maintaining genome stability and tumor suppression. [9][10][11][12][13] In the presence of double-strand break (DSBs), the protein complex composed of MRE11-RAD50-NBS1 (MRN) recruits and activates the ataxia-telangiectasiamutated (ATM) kinase at the vicinity of DSBs, 10 which leads to the phosphorylation of the histone variant H2AX (γH2AX). γH2AX decorates chromatin domains flanking DSBs, and is directly engaged by the mediator of DNA damage checkpoint 1 (MDC1). MDC1 loading onto the damaged chromatin subsequently permits the productive accumulation of a cohort of DNA damage signaling and mediator proteins. 14,15 In particular, the RING finger ubiquitin ligase RNF8 is targeted to MDC1 via its phospho-binding forkheadassociated domain, where it initiates a cascade of chromatin ubiquitination events important for tethering of DNA damage mediator and repair proteins, including 53BP1 and BRCA1, [16][17][18][19] the dysregulation of which compromises genome stability and cont...

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Regulation of DNA End Joining, Resection, and Immunoglobulin Class Switch Recombination by 53BP1

Cited by 213 publications

References 55 publications

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

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