Werner Helicase-interacting Protein 1 Binds Polyubiquitin via Its Zinc Finger Domain

DNA repair is regulated on many levels by ubiquitination. In order to identify novel connections between DNA repair pathways and ubiquitin signaling, we used mass spectrometry to identify proteins that interact with lysine 6-linked polyubiquitin chains. From this proteomic screen, we identified the DNA repair protein WRNIP1 (Werner helicase-interacting protein 1), along with nucleosome assembly protein 1, as novel ubiquitin-interacting proteins. We found that a small zinc finger domain at the N terminus of WRNIP1 is sufficient and necessary for noncovalent ubiquitin binding. This ubiquitin-binding zinc finger (UBZ) domain binds polyubiquitin but not monoubiquitin and appears to show no specificity for polyubiquitin chain linkage. A homologous zinc finger domain in RAD18 also binds polyubiquitin, suggesting a wider role for the UBZ domain in DNA repair. The WRNIP1 ubiquitin-binding function, along with its previously established ATPase activity, suggests that WRNIP1 plays a role in the metabolism of ubiquitinated proteins. Supporting this model, deletion of MGS1, the yeast homolog of WRNIP1, slows the rate of ubiquitin turnover, rendering yeast resistant to cycloheximide. We also find that WRNIP1 is heavily modified with ubiquitin and SUMO, revealing complex layers in the involvement of ubiquitin pathway proteins in the regulation of DNA repair. The novel ubiquitin-binding ability of WRNIP1 sheds light on the role of UBZ domain-containing proteins in postreplication DNA repair. DNA repair is regulated on many levels by ubiquitination. In order to identify novel connections between DNA repair pathways and ubiquitin signaling, we used mass spectrometry to identify proteins that interact with lysine 6-linked polyubiquitin chains. From this proteomic screen, we identified the DNA repair protein WRNIP1 (Werner helicase-interacting protein 1), along with nucleosome assembly protein 1, as novel ubiquitin-interacting proteins. We found that a small zinc finger domain at the N terminus of WRNIP1 is sufficient and necessary for noncovalent ubiquitin binding. This ubiquitin-binding zinc finger (UBZ) domain binds polyubiquitin but not monoubiquitin and appears to show no specificity for polyubiquitin chain linkage. A homologous zinc finger domain in RAD18 also binds polyubiquitin, suggesting a wider role for the UBZ domain in DNA repair. The WRNIP1 ubiquitin-binding function, along with its previously established ATPase activity, suggests that WRNIP1 plays a role in the metabolism of ubiquitinated proteins. Supporting this model, deletion of MGS1, the yeast homolog of WRNIP1, slows the rate of ubiquitin turnover, rendering yeast resistant to cycloheximide. We also find that WRNIP1 is heavily modified with ubiquitin and SUMO, revealing complex layers in the involvement of ubiquitin pathway proteins in the regulation of DNA repair. The novel ubiquitin-binding ability of WRNIP1 sheds light on the role of UBZ domain-containing proteins in postreplication DNA repair. Ubiquitination is an abundant post-translational modification that serves to regulate a wide variety of cellular pathways (1Shilatifard A. Annu. Rev. Biochem. 2006; 75: 243-269Crossref PubMed Scopus (898) Google Scholar, 2Huang T.T. D'Andrea A.D. Nat. Rev. Mol. Cell. Biol. 2006; 7: 323-334Crossref PubMed Scopus (222) Google Scholar, 3Chen Z.J. Nat. Cell. Biol. 2005; 7: 758-765Crossref PubMed Scopus (1026) Google Scholar). Ubiquitin, a 76-amino acid polypeptide, is conjugated to one or more lysine residues within a substrate protein via a multistep, multienzyme process (4Hershko A. Heller H. Elias S. Ciechanover A. J. Biol. Chem. 1983; 258: 8206-8214Abstract Full Text PDF PubMed Google Scholar). The consequences of ubiquitination for the substrate protein vary depending on the extent and type of ubiquitination. Monoubiquitination can lead to altered protein-protein interactions, relocalization, or the endocytosis of membrane-bound receptors (5Woelk T. Oldrini B. Maspero E. Confalonieri S. Cavallaro E. Di Fiore P.P. Polo S. Nat. Cell. Biol. 2006; 8: 1246-1254Crossref PubMed Scopus (162) Google Scholar, 6Hicke L. Riezman H. Cell. 1996; 84: 277-287Abstract Full Text Full Text PDF PubMed Scopus (671) Google Scholar). Ubiquitin can also undergo ubiquitination, leading to the formation of a polyubiquitin chain. Conjugation to a polyubiquitin chain in which the interubiquitin linkage occurs through Lys-48 generally results in the proteasome-mediated degradation of the substrate protein (7Chau V. Tobias J.W. Bachmair A. Marriott D. Ecker D.J. Gonda D.K. Varshavsky A. Science. 1989; 243: 1576-1583Crossref PubMed Scopus (1122) Google Scholar). Other types of polyubiquitin chain linkages do not appear to result in proteasomal degradation but instead play a signaling role in pathways, such as the inflammatory response (8Deng L. Wang C. Spencer E. Yang L. Braun A. You J. Slaughter C. Pickart C. Chen Z.J. Cell. 2000; 103: 351-361Abstract Full Text Full Text PDF PubMed Scopus (1524) Google Scholar) and DNA repair (9Spence J. Sadis S. Haas A.L. Finley D. Mol. Cell. Biol. 1995; 15: 1265-1273Crossref PubMed Google Scholar, 10Hofmann R.M. Pickart C.M. Cell. 1999; 96: 645-653Abstract Full Text Full Text PDF PubMed Scopus (672) Google Scholar, 11Hoege C. Pfander B. Moldovan G.L. Pyrowolakis G. Jentsch S. Nature. 2002; 419: 135-141Crossref PubMed Scopus (1751) Google Scholar). Several different DNA repair pathways have been shown to be regulated by ubiquitination. For example, the proper execution of nucleotide excision repair depends upon the polyubiquitination and degradation of a subset of its component enzymes (12Sugasawa K. Okuda Y. Saijo M. Nishi R. Matsuda N. Chu G. Mori T. Iwai S. Tanaka K. Hanaoka F. Cell. 2005; 121: 387-400Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar, 13Nag A. Bondar T. Shiv S. Raychaudhuri P. Mol. Cell. Biol. 2001; 21: 6738-6747Crossref PubMed Scopus (145) Google Scholar), whereas translesion DNA synthesis is regulated by the mono- and polyubiquitination of PCNA 3The abbreviations used are: PCNA, proliferating cell nuclear antigen; UBZ, ubiquitin-binding zinc finger; GFP, green fluorescent protein; AAA, ATPase associated with various activities; CCT, chaperonin containing TCP1; HA, hemagglutinin; HEK293, human embryonic kidney 293; HEK293T, human embryonic kidney 293 cells with SV40 large T antigen; LC-MS/MS, liquid chromatography coupled to tandem mass spectrometry; MAT, metal affinity tag; NAP1, nucleosome assembly protein 1; YPD, yeast extract/peptone/dextrose medium; MBP, maltose-binding protein; E1, ubiquitin-activating enzyme; E2, ubiquitin carrier protein; E3, ubiquitin-protein isopeptide ligase. (11Hoege C. Pfander B. Moldovan G.L. Pyrowolakis G. Jentsch S. Nature. 2002; 419: 135-141Crossref PubMed Scopus (1751) Google Scholar). BRCA1, which plays an essential role in several DNA repair pathways, catalyzes the formation of an unusual type of polyubiquitin chain linked through Lys-6 (14Wu-Baer F. Lagrazon K. Yuan W. Baer R. J. Biol. Chem. 2003; 278: 34743-34746Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). These Lys-6-linked polyubiquitin chains have been visualized at sites of DNA damage, perhaps serving as a scaffold for the assembly of DNA repair complexes (15Morris J.R. Solomon E. Hum. Mol. Genet. 2004; 13: 807-817Crossref PubMed Scopus (215) Google Scholar). To better understand the function of nondegradative polyubiquitin chains, we conducted a proteomic screen for proteins that interact with Lys-6-linked polyubiquitin chains. WRNIP1 (Werner helicase-interacting protein 1) and NAP1 (nucleosome assembly protein 1), were identified as candidate ubiquitin-interacting proteins through this screen. WRNIP1 was originally identified in a yeast screen through its with (Werner a for and K. J. A. M. Y. H. S. A. PubMed Scopus Google Scholar, H. Y. S. H. T. M. T. M. T. M. Y. M. 15: PubMed Scopus Google Scholar, Y. D. T. H. T. F. H. A. Y. M. T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). in WRNIP1 a small zinc finger at the N terminus and a ATPase domain in the of the The of WRNIP1 with the of along with its ability to DNA synthesis of suggests a role for WRNIP1 in DNA repair Y. D. T. H. T. F. H. A. Y. M. T. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, T. A. M. M. T. 2005; PubMed Scopus Google Scholar). of 1) been shown to be in postreplication DNA repair T. T. H. H. J. 2002; 21: PubMed Scopus Google Scholar). repair is a of the DNA response that that DNA the of that have the of or nucleotide excision repair J. Mol. Biol. PubMed Scopus Google Scholar). The ubiquitin complex is for the homologous pathway or the in which DNA the (11Hoege C. Pfander B. Moldovan G.L. Pyrowolakis G. Jentsch S. Nature. 2002; 419: 135-141Crossref PubMed Scopus (1751) Google Scholar). yeast suggests that postreplication repair T. T. H. H. J. 2002; 21: PubMed Scopus Google Scholar). that generally but to the and T. H. T. T. H. S. A. 2001; PubMed Scopus Google Scholar, T. T. Y. Y. H. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). This in DNA upon is on the of that an of the postreplication repair pathway T. T. Y. Y. H. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar). In this we show that WRNIP1 and RAD18 polyubiquitin through zinc finger This novel ubiquitin-binding suggests that WRNIP1 its function in postreplication repair by the of ubiquitinated proteins. by several yeast in pathways that regulate the of ubiquitinated proteins is altered to the protein synthesis PubMed Google Scholar, R. M. W. Mol. Biol. Cell. 8: PubMed Scopus Google Scholar). of ubiquitin is the protein to the for J. Finley D. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). in ubiquitin through ubiquitin or ubiquitin results in to J. Finley D. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). We find that have an of ubiquitin and to The that WRNIP1 and RAD18 polyubiquitin and the of ubiquitinated proteins the between the pathway and postreplication DNA repair. of been previously H. S. K. K. J. M. T. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). WRNIP1 was by and T. A. M. M. T. 2005; PubMed Scopus Google Scholar) as a The WRNIP1 was by the A NAP1 was by The RAD18 and WRNIP1 UBZ were by 1) for at and the DNA to to the of The was with and were by DNA or by mass spectrometry of the proteins. type yeast and a were the A. H. K. B. R. R. H. Chu C. K. F. M. F. E. G. T. M. H. N. D.J. A. M. N. P. M. C. C. L. P. B. M. S. S. M. G. R. K. K. P. M. Science. 1999; PubMed Scopus Google Scholar). were used in this and and and and 1) of and and an yeast and were was WRNIP1 were by with a of with the and The was by were conjugated to the or and and cells were as by DNA was the cells by or cells were with in in for and at in a for to cell was for on a at with The were at with and by mass spectrometry or by were to the and with the at was to the to a of This was with acid and with to the for proteins were an in and with of modified for at The was the by for with and with for in the of acid was to with were by an mass to a liquid in the of were to by and human protein by the to the R. 2004; PubMed Scopus Google Scholar). were conducted the mass mass of of ubiquitination of lysine and of and sites were identified with by K. C. F. 2004; Scholar). of of proteins identified by mass spectrometry was by the protein C.M. Y. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). In the of identified a protein is by that mass in and by and proteins as maltose-binding protein were on in to the proteins were on in Ubiquitin was by proteins with of ubiquitin or or polyubiquitin chains in for at were in and protein complexes were by for in of was by of with on containing the Ubiquitin yeast were in containing and were for as previously J. Finley D. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar). was on of the with 2006; of Scholar). for chains linked through Lys-6 have been in DNA signaling pathways (14Wu-Baer F. Lagrazon K. Yuan W. Baer R. J. Biol. Chem. 2003; 278: 34743-34746Abstract Full Text Full Text PDF PubMed Scopus (230) Google Scholar). In order to identify proteins that interact with Lys-6-linked polyubiquitin chains, we used a ubiquitin in which of the Lys-6 to H. S. K. K. J. M. T. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar) and an the This results in the of Lys-6-linked polyubiquitin chains and or proteins. were by of the with These were in a by liquid chromatography coupled to tandem mass spectrometry were a human protein with the R. 2004; PubMed Scopus Google Scholar). The results of Lys-6-linked ubiquitin lead to the of proteins that were in the and not the of the proteins were in A protein is at the protein have been a or to proteins were by protein C.M. Y. Mol. Cell. Biol. 2004; PubMed Scopus Google Scholar). of proteins can be as in ubiquitin metabolism This of proteins or ubiquitin-activating ubiquitin and proteins with previously identified ubiquitin-binding no of the were the that the is an abundant complex with several polyubiquitin receptors H. A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The of in this is to the nondegradative function of Lys-6-linked polyubiquitin pathway proteins Lys-6 ubiquitin ubiquitin protein domain containing degradation protein and domain containing protein type of domain-containing finger protein in a ubiquitin was the abundant protein identified in The and the for the of the that of the ubiquitin identified in this screen can the of the can be to suggesting that the ubiquitin of the ubiquitin in the of monoubiquitin or Lys-6-linked polyubiquitin chains. A proteins identified in the were to the and not be as pathway proteins. These proteins candidate ubiquitin-interacting proteins Lys-6 ubiquitin-interacting helicase-interacting protein assembly protein to protein to protein component protein protein protein protein protein protein protein protein protein ATPase domain-containing protein protein ATPase in a WRNIP1 and NAP1 with to the in the the candidate ubiquitin-interacting proteins WRNIP1, and NAP1 and and To that proteins with ubiquitin and to this is to Lys-6-linked polyubiquitin chains, we used the of ubiquitin H. S. K. K. J. M. T. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). of the at of the one lysine for polyubiquitin chain Ubiquitin were cells with the by the The were with and WRNIP1 To the of NAP1 with a NAP1 was that NAP1 be with was with the a were also with an the ubiquitin-activating one of the abundant pathway proteins identified the WRNIP1, and NAP1 with ubiquitin 1, A and was at levels in and cells and is a WRNIP1 and NAP1 were in of of the suggesting that the ubiquitin is not for Lys-6-linked chains. WRNIP1 was of been in the cellular response to DNA damage, but is its WRNIP1 was the abundant protein in the identified by WRNIP1 appears to a between DNA repair and ubiquitination, we to the WRNIP1 with WRNIP1 through its UBZ order to WRNIP1 is of noncovalent with we an in WRNIP1 and type human WRNIP1 was on and with monoubiquitin or polyubiquitin chains linked through Lys-48 or WRNIP1 and polyubiquitin chains. The noncovalent between WRNIP1 and was and no with monoubiquitin was WRNIP1 ubiquitin chains of or more ubiquitin that WRNIP1 a ubiquitin-binding We several to that the zinc finger domain is for the ability of WRNIP1 to A homologous zinc finger domain is found in a protein that as a ubiquitin and be to ubiquitin S. L. PubMed Scopus Google Scholar, V. S. S. L. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). a homolog of WRNIP1 in in which the zinc finger domain is by a which is to was that zinc finger in DNA and The zinc finger domain in was the ubiquitin-binding zinc finger (UBZ) domain M. C.M. N. F. G. B. P. G. M. K. Science. 2005; PubMed Scopus Google Scholar). on this we a in the WRNIP1 zinc finger domain to This in the UBZ domain ubiquitin in ubiquitin not with cells an of the WRNIP1 UBZ domain binds ubiquitin with the specificity as the protein These that the zinc finger domain of WRNIP1 is a UBZ which is necessary and sufficient for WRNIP1 polyubiquitin binding. The of human proteins as containing UBZ WRNIP1, the translesion synthesis DNA and the ubiquitin and a novel protein that we The RAD18 UBZ domain is as a A found that this zinc finger domain is sufficient and necessary for the of RAD18 to DNA S. L. S. N. K. Mori M. T. A. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). In light of the ubiquitin-binding function of the WRNIP1 UBZ domain as as the connections of RAD18 to the we the zinc finger domain in RAD18 also binds In ubiquitin that the RAD18 UBZ domain binds polyubiquitin in a to that of WRNIP1 WRNIP1 to UBZ that WRNIP1 as a or of on suggesting that WRNIP1 is to post-translational modification ubiquitin-binding proteins also conjugated to ubiquitin (5Woelk T. Oldrini B. Maspero E. Confalonieri S. Cavallaro E. Di Fiore P.P. Polo S. Nat. Cell. Biol. 2006; 8: 1246-1254Crossref PubMed Scopus (162) Google Scholar), in a process as coupled ubiquitination. we WRNIP1 is to a linkage to We and an to for the of conjugated A of ubiquitin-protein was at the mass of WRNIP1 The WRNIP1, which is or modified with ubiquitin and a of post-translational The ubiquitination of WRNIP1 is in the UBZ domain as is the with many ubiquitin WRNIP1 ubiquitination is on its ability to ubiquitin (5Woelk T. Oldrini B. Maspero E. Confalonieri S. Cavallaro E. Di Fiore P.P. Polo S. Nat. Cell. Biol. 2006; 8: 1246-1254Crossref PubMed Scopus (162) Google Scholar). The on which WRNIP1 is ubiquitinated were identified by to and by Ubiquitination sites can be identified through mass spectrometry by the mass and at the modified lysine R. Wang Y. R. 2002; PubMed Scopus Google Scholar). WRNIP1 spectrometry were a of with WRNIP1, were to a lysine with a mass of to in the of ubiquitinated A one of the ubiquitinated of WRNIP1 is shown in The ubiquitination sites the WRNIP1 In we have also a ubiquitination at lysine on the yeast homolog of WRNIP1 not sites identified on WRNIP1 by mass of in a In the of of WRNIP1 by mass we also identified and that WRNIP1 is modified with as as of WRNIP1 was by a of WRNIP1 WRNIP1 as a with a mass of a mass with the of a The between the WRNIP1 and the of ubiquitinated WRNIP1 suggests that modification with different of the protein WRNIP1 and we find that the UBZ domain WRNIP1 that is no ubiquitinated This of ubiquitin and levels suggests that regulate WRNIP1 Supporting this the WRNIP1 sites to the K. C. F. 2004; Scholar). The of sites is which was also identified as a ubiquitination in this the the between ubiquitination and be for the lysine the of of a ATPase domain and a ubiquitin-binding domain occurs in the protein serves to the degradation of ubiquitinated proteins by the by the polyubiquitin chains and with its ATPase domain C. M. J. 2004; PubMed Scopus Google Scholar). To WRNIP1 regulate the of ubiquitinated we to yeast for MGS1, the yeast homolog of WRNIP1, is T. H. T. T. H. S. A. 2001; PubMed Scopus Google Scholar). levels of between and WRNIP1 the the UBZ domain T. H. T. T. H. S. A. 2001; PubMed Scopus Google Scholar). also with the yeast homolog T. H. T. T. H. S. A. 2001; PubMed Scopus Google Scholar) and ubiquitin not of the of yeast that have in the of ubiquitinated proteins is to such as cycloheximide. In this results degradation of ubiquitin R. M. W. Mol. Biol. Cell. 8: PubMed Scopus Google Scholar). We find that resistant to on containing with a that protein ubiquitinated proteins appear to more in yeast in type yeast and These that the of yeast results a in the rate of of suggesting a previously role for in ubiquitin A for this we identified proteins that with Lys-6-linked polyubiquitin chains. of the proteins identified by mass spectrometry this screen or to function in the of the ubiquitin pathway proteins identified in the of ubiquitin to substrate whereas proteins were in the A proteins ubiquitin-binding of the ubiquitin pathway proteins identified function in the assembly and of polyubiquitin chains or the of mono- or polyubiquitin with no chain linkage We that the of to Lys-6-linked polyubiquitin chains in this screen can be to the of as with proteins that of more with These also that ubiquitin-interacting proteins chain specificity instead be by with the ubiquitinated protein or such as of the proteins identified in this screen not as in the We that the abundant candidate protein this screen that with WRNIP1, binds polyubiquitin through a zinc finger domain at its N we show that NAP1 with the of this to be proteins on the of ubiquitin-interacting proteins and of the chaperonin complex This complex is for the of a subset of cellular and V. 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N. K. Mori M. T. A. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, S. Y. S. H. M. S. A. 2000; PubMed Scopus Google Scholar). WRNIP1 and RAD18 interact with or ubiquitinated to role in repair WRNIP1 and RAD18 protein through the in with DNA repair through its ubiquitin S. Y. S. H. M. S. A. 2000; PubMed Scopus Google Scholar). the role of RAD18 in DNA repair is the of PCNA (11Hoege C. Pfander B. Moldovan G.L. Pyrowolakis G. Jentsch S. Nature. 2002; 419: 135-141Crossref PubMed Scopus (1751) Google Scholar), is that RAD18 in repair N. Mori M. H. T. H. S. M. T. PubMed Scopus Google Scholar) and that of its for proteasomal degradation S. S. K. K. K. H. M. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, L. Y. D. D. S. A. 2000; PubMed Scopus Google Scholar). In this we show that the of ubiquitinated proteins. for ubiquitinated proteins more the in The in protein is in and ubiquitinated proteins at a rate in type on a subset of proteins as a polyubiquitin The previously to proteins suggests that the ATPase of WRNIP1 to ubiquitinated proteins the DNA at sites of DNA damage, to the This the regulation by of DNA repair. RAD18 and appear to the function of polyubiquitin through UBZ and a of in the of proteins through the that the to DNA upon of is on the of is that the of proteins for degradation by ubiquitination at with the proteins degradation is by The UBZ and DNA to WRNIP1 and the translesion synthesis DNA and have been shown to ubiquitin through UBZ of UBZ domain-containing proteins in the repair of a of DNA UBZ protein with a function in the is that UBZ domain-containing protein function is also be in DNA repair. A identified by mass spectrometry in of the repair proteins and E. B. G. R. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The DNA repair function by UBZ proteins suggests that ubiquitin-binding the UBZ domain is for DNA repair. is that the UBZ domain with a DNA ubiquitinated the ability of the UBZ domain to types of polyubiquitin chains, as shown in this the specificity is more by the substrate protein a polyubiquitin chain PCNA is an candidate for the ubiquitinated scaffold on which UBZ domain-containing proteins and PCNA (11Hoege C. Pfander B. Moldovan G.L. Pyrowolakis G. Jentsch S. Nature. 2002; 419: 135-141Crossref PubMed Scopus (1751) Google Scholar, T. T. Y. Y. H. Mol. Cell. Biol. 2006; PubMed Scopus Google Scholar, L. B. J. L. S. Mol. Cell. Biol. 2001; 21: PubMed Scopus Google Scholar, L. J. L. S. Mol. Cell. Biol. 2002; PubMed Scopus Google Scholar). by which the UBZ domain proteins to in DNA repair is by the that for and the UBZ domain is sufficient and necessary for to DNA nuclear S. L. S. N. K. Mori M. T. A. J. Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar, S. R. J. 2006; PubMed Scopus Google Scholar, T. P. J. 2005; PubMed Scopus Google Scholar). The UBZ domain function in to repair sites upon a DNA the ubiquitin-binding of WRNIP1 and UBZ domain-containing proteins the to light on novel for the regulation of DNA repair. We and for of and for of the with