Genetic dissection of vertebrate 53BP1: A major role in non-homologous end joining of DNA double strand breaks

Nakamura, Kyoko; Sakai, Wataru; Kawamoto, Takuo; Bree, Ronan T.; Lowndes, Noel F.; Takeda, Shunichi; Taniguchi, Yoshihito

doi:10.1016/j.dnarep.2006.03.008

Cited by 101 publications

(87 citation statements)

References 29 publications

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“…Moreover, the function of ATM retention to chromatin is also likely to participate in DSBs repair. Both 53BP1 and SMC1 have been shown to participate in NHEJ both in vitro and in vivo (47,48,65,66). Here, we examined and found that like 53BP1 and SMC1, PTIP was involved in NHEJ, which further confirmed that PTIP functionally mediates, facilitates, and cooperates with 53BP1-ATM-SMC1 pathway for DNA DSBs repair.…”

Section: Discussionsupporting

confidence: 56%

PTIP Regulates 53BP1 and SMC1 at the DNA Damage Sites

Wu¹,

Prindle

Dressler

et al. 2009

Journal of Biological Chemistry

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Section: Discussionsupporting

confidence: 56%

PTIP Regulates 53BP1 and SMC1 at the DNA Damage Sites

Wu¹,

Prindle

Dressler

et al. 2009

Journal of Biological Chemistry

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“…1C). Although 53BP1-deficient cells have been shown to have a mild sensitivity to irradiation (29), 53BP1-depleted CH12F3-2 cells did not display increased sensitivity to irradiation compared with control cells (Fig. 1D).…”

Section: Resultsmentioning

confidence: 95%

The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination

Ramachandran

Chahwan

Nepal

et al. 2009

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

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An effective immune response requires B cells to produce several classes of antibodies through the process of class switch recombination (CSR). Activation-induced cytidine deaminase initiates CSR by deaminating deoxycytidines at switch regions within the Ig locus. This activity leads to double-stranded DNA break formation at the donor and recipient switch regions that are subsequently synapsed and ligated in a 53BP1-dependent process that remains poorly understood. The DNA damage response E3 ubiquitin ligases RNF8 and RNF168 were recently shown to facilitate recruitment of 53BP1 to sites of DNA damage. Here we show that the ubiquitination pathway mediated by RNF8 and RNF168 plays an integral part in CSR. Using the CH12F3-2 mouse B cell line that undergoes CSR to IgA at high rates, we demonstrate that knockdown of RNF8, RNF168, and 53BP1 leads to a significant decrease in CSR. We also show that 53BP1-deficient CH12F3-2 cells are protected from apoptosis mediated by the MDM2 inhibitor Nutlin-3. In contrast, deficiency in either E3 ubiquitin ligase does not protect cells from Nutlin-3-mediated apoptosis, indicating that RNF8 and RNF168 do not regulate all functions of 53BP1.53BP1 | activation-induced cytidine deaminase | DNA damage response P art of an effective immune response requires the production of antibodies of different classes, each of which mediates a different effector function. This process is initiated by activationinduced cytidine deaminase (AID), which induces class switch recombination (CSR) by deaminating deoxycytidines within Ig switch regions (1, 2). The recognition and subsequent processing of the mutated residues by base excision repair and/or mismatch repair machineries generates double-stranded DNA breaks (DSBs) at switch regions (3). In an attempt to mend the ensuing breaks, B cells mount a damage response similar to that signaled by irradiated cells (1). Ultimately, AID-induced DSBs are repaired predominantly by nonhomologous end-joining (4, 5) and to a lesser extent by an alternative end-joining pathway (6).Generally, DSBs are readily recognized by sensor-kinase protein complexes, including the Mre11-Rad50-Nbs1 (MRN)/ataxiatelangiectasia mutated (ATM), Ku70/Ku80-DNA-PKcs, and ataxiatelangiectasia and Rad3-related (ATR)-ATR-interacting protein complexes (7). Upon binding to a DSB site, these factors are activated to trigger a cascade of events that culminates in cell cycle delay and/or DNA repair (7). During this process, sequential chromatin modifications around the break sites appear to be crucial for adequate resolution of the DNA breaks. Active chromatin modification is initiated by ATM-dependent phosphorylation of the histone variant H2AX to the γH2AX form (8-10). γ-H2AX then preferentially binds the tandem-BRCA1 C-terminal domain (BRCT) motifs of mediator of DNA damage checkpoint 1 (MDC1) (11, 12), which in turn recruits more MRN/ATM, thereby amplifying the γ-H2AX signal (11, 12). Recently, it was shown that ATM also phosphorylates MDC1 at a TQxF consensus, allowing for the recruitmen...

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“…53BP1 accumulates at DSBs (18), and is involved in DNA repair through its essential role in nonhomologous end joining (8,19). We reasoned that the interaction between 53BP1 and methylated K810 may contribute to the role of pRb in DNA repair.…”

Section: Significancementioning

confidence: 99%

Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor

Carr

Munro

Zalmas

et al. 2014

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

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The retinoblastoma tumor suppressor protein pRb is a key regulator of cell cycle progression and mediator of the DNA damage response. Lysine methylation at K810, which occurs within a critical Cdk phosphorylation motif, holds pRb in the hypophosphorylated growth-suppressing state. We show here that methyl K810 is read by the tandem tudor domain containing tumor protein p53 binding protein 1 (53BP1). Structural elucidation of 53BP1 in complex with a methylated K810 pRb peptide emphasized the role of the 53BP1 tandem tudor domain in recognition of the methylated lysine and surrounding residues. Significantly, binding of 53BP1 to methyl K810 occurs on E2 promoter binding factor target genes and allows pRb activity to be effectively integrated with the DNA damage response. Our results widen the repertoire of cellular targets for 53BP1 and suggest a previously unidentified role for 53BP1 in regulating pRb tumor suppressor activity.T he retinoblastoma tumor suppressor protein pRb is either directly mutated or functionally inactivated in the vast majority of human tumors (1). One of its principle roles in cells is to regulate transcription, and the E2 promoter binding factor (E2F) family of transcription factors represents one of its most important targets (2). E2F acts to regulate the expression of a variety of genes connected with cell cycle progression and cell fate (including apoptosis, senescence, and differentiation), and the physical interaction between pRb and E2F hinders transcriptional activation by E2F, which coincides with cell cycle arrest (2, 3).The tumor suppressor activity of pRb and its interaction with E2F is regulated by posttranslational modifications (4). For example, multiple cyclin-dependent kinase (Cdk) phosphorylation events occur within pRb, and pRb phosphorylation is temporally regulated as cells progress through the cell cycle, which disrupts the interaction between pRb and E2F. Other types of modification, such as acetylation in the C-terminal region, are also known to influence pRb activity (5).More recently, a role for lysine (K) methylation in pRb control has been described (6). Thus, residue K810 undergoes methylation mediated by SET [su(var), enhancer-of-zeste, trithorax] domain containing lysine methyltransferase 7 (Set7/9) (also known as SETD7/KMT7) (6). Monomethylation at K810 holds pRb in the hypophosphorylated growth suppressing state, which occurs at a mechanistic level by inhibiting the physical association of Cdk complexes with pRb and thereby blocks Cdk-dependent phosphorylation (6). This is because, in the unmethylated state, K810 acts as the essential basic residue in the Cdk consensus phosphorylation site S807 (namely SPLK, Fig. 1A), which is an early pRb phosphorylation event during cell cycle control (7). Significantly, methylation of K810 hinders recognition and subsequent phosphorylation of S807 by cyclin/ Cdk complexes (6).Here, we have elucidated a previously unidentified level of regulation imposed on pRb mediated by the methylation event at K810. In addition to inhi...

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Genetic dissection of vertebrate 53BP1: A major role in non-homologous end joining of DNA double strand breaks

Cited by 101 publications

References 29 publications

PTIP Regulates 53BP1 and SMC1 at the DNA Damage Sites

PTIP Regulates 53BP1 and SMC1 at the DNA Damage Sites

The RNF8/RNF168 ubiquitin ligase cascade facilitates class switch recombination

Lysine methylation-dependent binding of 53BP1 to the pRb tumor suppressor

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