hSnm1 Colocalizes and Physically Associates with 53BP1 before and after DNA Damage

Richie, Christopher T.; Peterson, Carolyn A.; Lü, Tao; Hittelman, Walter N.; Carpenter, Phillip B.; Legerski, Randy J.

doi:10.1128/mcb.22.24.8635-8647.2002

Cited by 40 publications

(45 citation statements)

References 55 publications

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“…53BP1 has been reported to interact with Cdc27, a component of the anaphase-promoting complex (34). Intriguingly, the Artemis-related protein Snm1 has also been reported to associate with 53BP1 and coimmunoprecipitates with Cdc27 (31,35). It is thus possible that 53BP1 influences anaphase-promoting complex function, a result that would conceivably alter cell-cycle control in both mitosis and interphase.…”

Section: Discussionmentioning

confidence: 99%

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Morales

Franco

Murphy

et al. 2006

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

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p53-binding protein 1 (53BP1) participates in the cellular response to DNA double-stranded breaks where it associates with various DNA repair͞cell cycle factors including the H2AX histone variant. Mice deficient for 53BP1 (53BP1 ؊/؊ ) are sensitive to ionizing radiation and immunodeficient because of impaired Ig heavy chain class switch recombination. Here we show that, as compared with p53 ؊/؊ mice, 53BP1 ؊/؊ ͞p53 ؊/؊ animals more rapidly develop tumors, including T cell lymphomas and, at lower frequency, B lineage lymphomas, sarcomas, and teratomas. In addition, T cells from animals deficient for both 53BP1 and p53 (53BP1 ؊/؊ ͞p53 ؊/؊ ) display elevated levels of genomic instability relative to T cells deficient for either 53BP1 or p53 alone. In contrast to p53 ؊/؊ T cell lymphomas, which routinely display aneuploidy but not translocations, 53BP1 ؊/؊ ͞p53 ؊/؊ thymic lymphomas fall into two distinct cytogenetic categories, with many harboring clonal translocations (40%) and the remainder showing aneuploidy (60%). We propose that 53BP1, in the context of p53 deficiency, suppresses T cell lymphomagenesis through its roles in both cell-cycle checkpoints and double-stranded break repair.thymic lymphoma ͉ aneuploidy ͉ translocations D ouble-stranded break (DSB) repair is essential for genomic stability and tumor suppression. In mammalian cells, DSBs arise through exogenous means such as ionizing radiation, at stalled replication forks, and in the context of two genetically programmed processes that occur in lymphoid cells (1-3). DSBs are repaired by either of two nonmutually exclusive mechanisms: homologous recombination and nonhomologous end joining. During the development of the immune system, both B and T cells assemble the exons that encode Igs and T cell receptor variable regions by means of V(D)J recombination. In addition, mature B cells can express different Ig heavy chain constant regions through a DSB-mediated process known as Ig heavy chain class switch recombination (CSR). The DSBs that initiate V(D)J recombination are generated by the site-specific RAG endonuclease, whereas those that initiate CSR appear to involve the activation-induced deaminase. However, both V(D)J recombination and CSR are completed by nonhomologous end joining. In contrast to V(D)J recombination, CSR requires components of the DNA DSB repair response, including the histone variant H2AX and p53 binding protein 1 (53BP1) (4-7), potentially to juxtapose broken DSBs for nonhomologous end joining (8). Although 53BP1 is required for joining of S regions during CSR, like H2AX, it does not appear to be absolutely required for V(D)J recombination (6, 7), perhaps because of the fact that RAG also mediates synapsis functions (8).53BP1 is phosphorylated in response to ionizing radiation, accumulates at or near sites of DNA damage, and participates in the intra S and G 2 ͞M checkpoints (reviewed in ref. 9). Accumulation of 53BP1 at sites of irradiation-induced foci depends on

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Section: Discussionmentioning

confidence: 99%

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Morales

Franco

Murphy

et al. 2006

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

Self Cite

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“…Nonetheless, a function in DSB repair is not completely excluded because it is not clear if these mSNM1 À/À ES cells represent a null phenotype (Dronkert et al, 2000). In addition, the fraction of human cells containing hSNM1 foci increases dramatically following exposure to IR, and in these foci hSNM1 is reported to colocalize with 53BP1 (Richie et al, 2002), a molecule clearly involved in the signaling of DSBs. Therefore, there is at least circumstantial evidence that all three PSO2 homologs, hSNM1, SNM1B and hSNM1C/ARTEMIS, may be involved in DSB repair.…”

Section: Discussionmentioning

confidence: 99%

“…Treatment with IR or MMC resulted in an increased number of nuclei with multiple foci, and a concomitant decrease in the number of large body-containing nuclei. In addition, hSNM1 colocalized in a DNA damage-independent manner with 53BP1, a protein that plays a role in the cellular response to IR, although the functional significance of this finding was unclear (Richie et al, 2002).…”

Section: Introductionmentioning

confidence: 98%

“…Mouse embryonic stem (ES) cells with disrupted mSNM1 display a twofold increase in their sensitivity to MMC, but not to other DNA crosslinking agents (Dronkert et al, 2000). Richie et al (2002) characterized the subcellular distribution of hSNM1 using indirect immunofluorescence. Exclusively nuclear expression was observed, with three different patterns, either diffusely distributed, localized within multiple punctate foci or forming one or two larger bodies.…”

Section: Introductionmentioning

confidence: 99%

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Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

2004

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DNA interstrand crosslinks (ICLs) are critical lesions for the mammalian cell since they affect both DNA strands and block transcription and replication. The repair of ICLs in the mammalian cell involves components of different repair pathways such as nucleotide-excision repair and the double-strand break/homologous recombination repair pathways. However, the mechanistic details of mammalian ICL repair have not been fully delineated. We describe here the complete coding sequence and the genomic organization of hSNM1B, one of at least three human homologs of the Saccharomyces cerevisiae PSO2 gene. Depletion of hSNM1B by RNA interference rendered cells hypersensitive to ICL-inducing agents. This requirement for hSNM1B in the cellular response to ICL has been hypothesized before but never experimentally verified. In addition, siRNA knockdown of hSNM1B rendered cells sensitive to ionizing radiation, suggesting the possibility of hSNM1B involvement in homologous recombination repair of double-strand breaks arising as intermediates of ICL repair. Monoubiquitination of FANCD2, a key step in the FANC/BRCA pathway, is not affected in hSNM1B-depleted HeLa cells, indicating that hSNM1B is probably not a part of the Fanconi anemia core complex. Nonetheless, similarities in the phenotype of hSNM1B-depleted cells and cultured cells from patients suffering from Fanconi anemia make hSNM1B a candidate for one of the as yet unidentified Fanconi anemia genes not involved in monoubiquitination of FANCD2.

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“…Snm1A localizes to DNA double-strand breaks after ionizing radiation; although cells lacking Snm1A are sensitive only to mitomycin C and not ionizing radiation (23,24). Snm1A co-localizes with the DNA damage response protein 53BP before and after exposure to ionizing radiation (23).…”

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confidence: 99%

hSnm1B Is a Novel Telomere-associated Protein

Freibaum

Counter

2006

Journal of Biological Chemistry

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Artemis, a member of the ␤-CASP family, has been implicated in the regulation of both telomere stability and length. Prompted by this, we examined whether the other two putative DNA-binding members of this family, hSnm1A and hSnm1B, may associate with telomeres. hSnm1A was found to not interact with the telomere. Conversely, hSnm1B was found to associate with telomeres in vivo by both immunofluorescence and chromatin immunoprecipitation. Furthermore, the C terminus of hSnm1B was shown to interact with the TRF homology domain of TRF2 indicating that hSnm1B is likely recruited to the telomere via interaction with the doublestranded telomere-binding protein TRF2.The ends of human chromosomes are capped and protected by a DNAprotein structure termed the telomere. The DNA portion of human telomeres is composed of a G-rich repeat (TTAGGG) that extends past the complementary C-rich strand, forming a 3Ј extension. This extension has been found by electron microscopy to loop back and invade the double-stranded region, forming a large loop structure termed the t-loop (1). The protein portion of telomeres is composed of a core of six proteins termed the telosome or shelterin (2-4), three of which directly bind telomeric DNA, TRF1 (5), TRF2 (6, 7), and hPot1 (8), and three that associate with the DNA-binding proteins, Tin2 (9), Tpp1 (10 -12), and Rap1 (13). TRF1 and TRF2 bind double-stranded telomeric DNA (7), whereas hPot1 binds the single-stranded region of the telomere (8). In addition to this core complex, many other proteins are known to associate and function at the telomere, albeit at a smaller concentration and often indirectly through binding to TRF1 or TRF2 (4).One protein that influences the stability of the telomere but is not a member of the described core telomeric complex is Artemis. This protein is a member of the ␤-CASP family of proteins that contain a unique metallo-␤-lactamase domain that hydrolyzes nucleic acids (14). Artemis is well established to play a role in non-homologous recombination where it forms a complex with DNA-PK CS , which cleaves the intermediate hairpin loop structure formed during V(D)J recombination and non-homologous end joining (15). However, Artemis-deficient mice have increased telomeric fusions, suggesting that this family of proteins plays a role in telomere structure or function (16). Indeed, Artemis deficient cell lines have increased rates of telomeric shortening as well as rapid accumulation of anaphase bridges (17).Five mammalian proteins belonging to the ␤-CASP family have been identified, two of which hydrolyze RNA (18 -21), whereas the remaining three, Artemis, Snm1A, and Snm1B, are believed to function solely on DNA substrates (22). Snm1A localizes to DNA double-strand breaks after ionizing radiation; although cells lacking Snm1A are sensitive only to mitomycin C and not ionizing radiation (23,24). Snm1A co-localizes with the DNA damage response protein 53BP before and after exposure to ionizing radiation (23). Snm1A is also highly up-regulated during mitosis and is be...

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hSnm1 Colocalizes and Physically Associates with 53BP1 before and after DNA Damage

Cited by 40 publications

References 55 publications

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

53BP1 and p53 synergize to suppress genomic instability and lymphomagenesis

Human SNM1B is required for normal cellular response to both DNA interstrand crosslink-inducing agents and ionizing radiation

hSnm1B Is a Novel Telomere-associated Protein

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