The β-lactamase motif in Snm1 is required for repair of DNA double-strand breaks caused by interstrand crosslinks in S. cerevisiae

Li, Xiaorong; Moses, Robb E.

doi:10.1016/s1568-7864(02)00192-1

Cited by 53 publications

(64 citation statements)

References 23 publications

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“…More recent reports have suggested that yeast SNM1 acts in a different epistasis group than do REV3 and RAD51 for ICL repair (9,14). We carried out similar epistasis analysis using DT40 cells and found that SNM1A was not epistatic with XRCC3 (HR), RAD18 (TLS), or FANCC (FA).…”

Section: Discussionmentioning

confidence: 75%

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DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

Ishiai

Kimura

Namikoshi

et al. 2004

Molecular and Cellular Biology

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The yeast SNM1/PSO2 gene specifically functions in DNA interstrand cross-link (ICL) repair, and its role has been suggested to be separate from other DNA repair pathways. In vertebrates, there are three homologs of SNM1 (SNM1A, SNM1B, and SNM1C/Artemis; SNM1 family proteins) whose functions are largely unknown. We disrupted each of the SNM1 family genes in the chicken B-cell line DT40. Both SNM1A-and SNM1B-deficient cells were sensitive to cisplatin but not to X-rays, whereas SNM1C/Artemis-deficient cells exhibited sensitivity to X-rays but not to cisplatin. SNM1A was nonepistatic with XRCC3 (homologous recombination), RAD18 (translesion synthesis), FANCC (Fanconi anemia), and SNM1B in ICL repair. SNM1A protein formed punctate nuclear foci depending on the conserved SNM1 (metallo-␤-lactamase) domain. PIAS1 was found to physically interact with SNM1A, and they colocalized at nuclear foci. Point mutations in the SNM1 domain, which disrupted the interaction with PIAS1, led to mislocalization of SNM1A in the nucleus and loss of complementation of snm1a cells. These results suggest that interaction between SNM1A and PIAS1 is required for ICL repair.DNA interstrand cross-links (ICLs) covalently bind the two complementary strands of the double helix of DNA. They severely impair fundamental processes of DNA metabolism such as transcription or replication, leading to cell death if they are left unrepaired. Current protocols for cancer chemotherapy often include ICL-inducing agents, i.e., mitomycin C (MMC) or cisplatin, for effective killing of malignant cells (reviewed in references 7 and 21).The molecular mechanism of ICL repair is still poorly understood. In the yeast Saccharomyces cerevisiae, three distinct pathways, including nucleotide excision repair (NER), homologous recombination (HR), and translesion synthesis (TLS), participate in ICL repair (7,20). In addition, yeast SNM1 (also known as PSO2) specifically functions in ICL repair without apparently participating directly in any of these pathways (2, 9). During the repair process, NER mediates incisions on both sides of the cross-linked DNA (sometimes termed "unhooking") (5), and double-strand breaks (DSBs), which are probably associated with the collapse of a replication fork, are formed. The DSBs are then repaired by HR mechanisms. The interdependence between unhooking and formation of DSBs remains unclear (7). Yeast snm1 mutants are proficient in unhooking but are unable to process DSB intermediates (7,19,40).In mammalian cells, the situation is even more complex.Among NER factors, XPF/ERCC1 endonuclease appears to be particularly important for the unhooking of ICLs (5,21,26,32). Hamster mutant cells lacking the RAD51 paralog XRCC2 or XRCC3 display extreme sensitivity to ICLs, indicating an important role of HR in mammalian ICL repair (17). Cells from Fanconi anemia (FA) patients are also highly sensitive to ICL reagents (33), but the role of FA proteins in ICL repair is still unclear (4). Furthermore, there are three homologs of SNM1 (referred to as SNM1A, S...

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Section: Discussionmentioning

confidence: 75%

“…Taken together, these experiments suggest that the SNM1 domain of SNM1A, along with focus formation, is required for cisplatin tolerance. Consistently, the ICL repair function of yeast SNM1 also depends on the SNM1 domain (14). Two-hybrid screening for SNM1A-interacting factors.…”

Section: Resultsmentioning

confidence: 81%

DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

Ishiai

Kimura

Namikoshi

et al. 2004

Molecular and Cellular Biology

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“…On one hand, since Artemis can cleave single-stranded DNA loop structures (15), it is possible that hSnm1B may play a role in processing the telomeric t-loop structure. Alternatively, as the budding yeast SNM1 possesses 5Ј-exonuclease activity in vitro (33,34), perhaps hSnm1B generates the single-stranded 3Ј overhang at the end of the telomere. Nevertheless, the association of hSnm1B with telomeres argues that this protein is likely performing some function critical to telomere structure or function.…”

Section: Discussionmentioning

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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“…The molecular function of yeast Snm1 remains poorly defined. Mutants of snm1/ pso2 appear normal in the initial processing steps of interstrand cross-link (ICL) repair, but are defective in the resolution of double-strand breaks (DSBs) that occur presumably as a consequence of replication fork collapse in response to ICLs (Magana-Schwencke et al, 1982;Wilborn and Brendel, 1989;Li and Moses, 2003;Barber et al, 2005). Interestingly, Snm1 has been shown to have an overlapping role with the 5 0 -3 0 mismatch repair exonuclease Exo1 during processing of collapsed replication forks via homologous recombination (Barber et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links

et al. 2008

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The removal of DNA interstrand cross-links (ICLs) has proven to be notoriously complicated due to the involvement of multiple pathways of DNA repair, which include the Fanconi anemia/BRCA pathway, homologous recombination and components of the nucleotide excision and mismatch repair pathways. Members of the SNM1 gene family have also been shown to have a role in mediating cellular resistance to ICLs, although their precise function has remained elusive. Here, we show that knockdown of Snm1B/Apollo in human cells results in hypersensitivity to mitomycin C (MMC), but not to IR. We also show that Snm1B-deficient cells exhibit a defective S phase checkpoint in response to MMC, but not to IR, and this finding may account for the specific sensitivity to the cross-linking drug. Interestingly, although previous studies have largely implicated ATR as the major kinase activated in response to ICLs, we show that it is activation of the ATMmediated checkpoint that is defective in Snm1B-deficient cells. The requirement for Snm1B in ATM checkpoint activation specifically after ICL damage is correlated with its role in promoting double-strand break formation, and thus replication fork collapse. Consistent with this result Snm1B was found to interact directly with Mus81-Eme1, an endonuclease previously implicated in fork collapse. In addition, we also show that Snm1B interacts with the Mre11-Rad50-Nbs1 (MRN) complex and with FancD2 further substantiating its role as a checkpoint/DNA repair protein.

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The β-lactamase motif in Snm1 is required for repair of DNA double-strand breaks caused by interstrand crosslinks in S. cerevisiae

Cited by 53 publications

References 23 publications

DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

DNA Cross-Link Repair Protein SNM1A Interacts with PIAS1 in Nuclear Focus Formation

hSnm1B Is a Novel Telomere-associated Protein

Snm1B/Apollo mediates replication fork collapse and S Phase checkpoint activation in response to DNA interstrand cross-links

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