Several factors that participate in DNA damage response and repair are SUMOylated (reviewed in Dou et al. 2011, Bekker-Jensen and Mailand 2011, Ulrich 2012, Psakhye and Jentsch 2012, Bologna and Ferrari 2013, Flotho and Melchior 2013, Jackson and Durocher 2013). SUMOylation can alter enzymatic activity and protein stability or it can serve to recruit additional factors. For example, SUMOylation of Thymine DNA glycosylase (TDG) causes TDG to lose affinity for its product, an abasic site opposite a G residue, and thus increases turnover of the enzyme. During repair of double-strand breaks SUMO1, SUMO2, SUMO3, and the SUMO E3 ligases PIAS1 and PIAS4 accumulate at double-strand breaks where BRCA1, HERC1, RNF168, MDC1, and TP53BP1 are SUMOylated. SUMOylation of BRCA1 may increase its ubiquitin ligase activity while SUMOylation of MDC1 and HERC2 appears to play a role in recruitment of proteins such as RNF4 and RNF8 to double strand breaks. Similarly SUMOylation of RPA1 (RPA70) recruits RAD51 in the homologous recombination pathway.
View original pathway at Reactome.
Galisson F, Mahrouche L, Courcelles M, Bonneil E, Meloche S, Chelbi-Alix MK, Thibault P.; ''A novel proteomics approach to identify SUMOylated proteins and their modification sites in human cells.''; PubMedEurope PMCScholia
Ouyang KJ, Woo LL, Zhu J, Huo D, Matunis MJ, Ellis NA.; ''SUMO modification regulates BLM and RAD51 interaction at damaged replication forks.''; PubMedEurope PMCScholia
Gong L, Yeh ET.; ''Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3.''; PubMedEurope PMCScholia
Yin Y, Seifert A, Chua JS, Maure JF, Golebiowski F, Hay RT.; ''SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage.''; PubMedEurope PMCScholia
Everett RD, Lomonte P, Sternsdorf T, van Driel R, Orr A.; ''Cell cycle regulation of PML modification and ND10 composition.''; PubMedEurope PMCScholia
Vertegaal AC, Ogg SC, Jaffray E, Rodriguez MS, Hay RT, Andersen JS, Mann M, Lamond AI.; ''A proteomic study of SUMO-2 target proteins.''; PubMedEurope PMCScholia
Flotho A, Melchior F.; ''Sumoylation: a regulatory protein modification in health and disease.''; PubMedEurope PMCScholia
Zilio N, Williamson CT, Eustermann S, Shah R, West SC, Neuhaus D, Ulrich HD.; ''DNA-dependent SUMO modification of PARP-1.''; PubMedEurope PMCScholia
Bologna S, Ferrari S.; ''It takes two to tango: Ubiquitin and SUMO in the DNA damage response.''; PubMedEurope PMCScholia
Knipscheer P, Flotho A, Klug H, Olsen JV, van Dijk WJ, Fish A, Johnson ES, Mann M, Sixma TK, Pichler A.; ''Ubc9 sumoylation regulates SUMO target discrimination.''; PubMedEurope PMCScholia
Lamoliatte F, Bonneil E, Durette C, Caron-Lizotte O, Wildemann D, Zerweck J, Wenshuk H, Thibault P.; ''Targeted identification of SUMOylation sites in human proteins using affinity enrichment and paralog-specific reporter ions.''; PubMedEurope PMCScholia
Fu C, Ahmed K, Ding H, Ding X, Lan J, Yang Z, Miao Y, Zhu Y, Shi Y, Zhu J, Huang H, Yao X.; ''Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3.''; PubMedEurope PMCScholia
Tammsalu T, Matic I, Jaffray EG, Ibrahim AFM, Tatham MH, Hay RT.; ''Proteome-wide identification of SUMO2 modification sites.''; PubMedEurope PMCScholia
Tatham MH, Kim S, Jaffray E, Song J, Chen Y, Hay RT.; ''Unique binding interactions among Ubc9, SUMO and RanBP2 reveal a mechanism for SUMO paralog selection.''; PubMedEurope PMCScholia
Baba D, Maita N, Jee JG, Uchimura Y, Saitoh H, Sugasawa K, Hanaoka F, Tochio H, Hiroaki H, Shirakawa M.; ''Crystal structure of thymine DNA glycosylase conjugated to SUMO-1.''; PubMedEurope PMCScholia
Cremona CA, Sarangi P, Zhao X.; ''Sumoylation and the DNA damage response.''; PubMedEurope PMCScholia
Martin N, Schwamborn K, Schreiber V, Werner A, Guillier C, Zhang XD, Bischof O, Seeler JS, Dejean A.; ''PARP-1 transcriptional activity is regulated by sumoylation upon heat shock.''; PubMedEurope PMCScholia
Taylor EM, Copsey AC, Hudson JJ, Vidot S, Lehmann AR.; ''Identification of the proteins, including MAGEG1, that make up the human SMC5-6 protein complex.''; PubMedEurope PMCScholia
Baba D, Maita N, Jee JG, Uchimura Y, Saitoh H, Sugasawa K, Hanaoka F, Tochio H, Hiroaki H, Shirakawa M.; ''Crystal structure of SUMO-3-modified thymine-DNA glycosylase.''; PubMedEurope PMCScholia
Danielsen JR, Povlsen LK, Villumsen BH, Streicher W, Nilsson J, Wikström M, Bekker-Jensen S, Mailand N.; ''DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc finger.''; PubMedEurope PMCScholia
Psakhye I, Jentsch S.; ''Protein group modification and synergy in the SUMO pathway as exemplified in DNA repair.''; PubMedEurope PMCScholia
Sternsdorf T, Jensen K, Reich B, Will H.; ''The nuclear dot protein sp100, characterization of domains necessary for dimerization, subcellular localization, and modification by small ubiquitin-like modifiers.''; PubMedEurope PMCScholia
Galanty Y, Belotserkovskaya R, Coates J, Polo S, Miller KM, Jackson SP.; ''Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaks.''; PubMedEurope PMCScholia
Woods YL, Xirodimas DP, Prescott AR, Sparks A, Lane DP, Saville MK.; ''p14 Arf promotes small ubiquitin-like modifier conjugation of Werners helicase.''; PubMedEurope PMCScholia
Matafora V, D'Amato A, Mori S, Blasi F, Bachi A.; ''Proteomics analysis of nucleolar SUMO-1 target proteins upon proteasome inhibition.''; PubMedEurope PMCScholia
Su HL, Li SS.; ''Molecular features of human ubiquitin-like SUMO genes and their encoded proteins.''; PubMedEurope PMCScholia
Eladad S, Ye TZ, Hu P, Leversha M, Beresten S, Matunis MJ, Ellis NA.; ''Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification.''; PubMedEurope PMCScholia
Impens F, Radoshevich L, Cossart P, Ribet D.; ''Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuli.''; PubMedEurope PMCScholia
Suntharalingam M, Wente SR.; ''Peering through the pore: nuclear pore complex structure, assembly, and function.''; PubMedEurope PMCScholia
Rabut G, Doye V, Ellenberg J.; ''Mapping the dynamic organization of the nuclear pore complex inside single living cells.''; PubMedEurope PMCScholia
Potts PR, Porteus MH, Yu H.; ''Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaks.''; PubMedEurope PMCScholia
Vialter A, Vincent A, Demidem A, Morvan D, Stepien G, Venezia ND, Rio PG.; ''Cell cycle-dependent conjugation of endogenous BRCA1 protein with SUMO-2/3.''; PubMedEurope PMCScholia
Bekker-Jensen S, Mailand N.; ''The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaks.''; PubMedEurope PMCScholia
Yurchenko V, Xue Z, Sadofsky MJ.; ''SUMO modification of human XRCC4 regulates its localization and function in DNA double-strand break repair.''; PubMedEurope PMCScholia
Dou H, Huang C, Van Nguyen T, Lu LS, Yeh ET.; ''SUMOylation and de-SUMOylation in response to DNA damage.''; PubMedEurope PMCScholia
Hardeland U, Steinacher R, Jiricny J, Schär P.; ''Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnover.''; PubMedEurope PMCScholia
Cronshaw JM, Krutchinsky AN, Zhang W, Chait BT, Matunis MJ.; ''Proteomic analysis of the mammalian nuclear pore complex.''; PubMedEurope PMCScholia
Pichler A, Gast A, Seeler JS, Dejean A, Melchior F.; ''The nucleoporin RanBP2 has SUMO1 E3 ligase activity.''; PubMedEurope PMCScholia
Dou H, Huang C, Singh M, Carpenter PB, Yeh ET.; ''Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complex.''; PubMedEurope PMCScholia
Morris JR, Boutell C, Keppler M, Densham R, Weekes D, Alamshah A, Butler L, Galanty Y, Pangon L, Kiuchi T, Ng T, Solomon E.; ''The SUMO modification pathway is involved in the BRCA1 response to genotoxic stress.''; PubMedEurope PMCScholia
Wang QE, Praetorius-Ibba M, Zhu Q, El-Mahdy MA, Wani G, Zhao Q, Qin S, Patnaik S, Wani AA.; ''Ubiquitylation-independent degradation of Xeroderma pigmentosum group C protein is required for efficient nucleotide excision repair.''; PubMedEurope PMCScholia
Jackson SP, Durocher D.; ''Regulation of DNA damage responses by ubiquitin and SUMO.''; PubMedEurope PMCScholia
Kamitani T, Nguyen HP, Kito K, Fukuda-Kamitani T, Yeh ET.; ''Covalent modification of PML by the sentrin family of ubiquitin-like proteins.''; PubMedEurope PMCScholia
Xu J, Watkins T, Reddy A, Reddy ES, Rao VN.; ''A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cells.''; PubMedEurope PMCScholia
Gao C, Ho CC, Reineke E, Lam M, Cheng X, Stanya KJ, Liu Y, Chakraborty S, Shih HM, Kao HY.; ''Histone deacetylase 7 promotes PML sumoylation and is essential for PML nuclear body formation.''; PubMedEurope PMCScholia
Steinacher R, Schär P.; ''Functionality of human thymine DNA glycosylase requires SUMO-regulated changes in protein conformation.''; PubMedEurope PMCScholia
Sternsdorf T, Jensen K, Will H.; ''Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1.''; PubMedEurope PMCScholia
Kosinski J, Mosalaganti S, von Appen A, Teimer R, DiGuilio AL, Wan W, Bui KH, Hagen WJ, Briggs JA, Glavy JS, Hurt E, Beck M.; ''Molecular architecture of the inner ring scaffold of the human nuclear pore complex.''; PubMedEurope PMCScholia
Saito K, Kagawa W, Suzuki T, Suzuki H, Yokoyama S, Saitoh H, Tashiro S, Dohmae N, Kurumizaka H.; ''The putative nuclear localization signal of the human RAD52 protein is a potential sumoylation site.''; PubMedEurope PMCScholia
Wang QE, Zhu Q, Wani G, El-Mahdy MA, Li J, Wani AA.; ''DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiation.''; PubMedEurope PMCScholia
Praefcke GJ, Hofmann K, Dohmen RJ.; ''SUMO playing tag with ubiquitin.''; PubMedEurope PMCScholia
Luo K, Zhang H, Wang L, Yuan J, Lou Z.; ''Sumoylation of MDC1 is important for proper DNA damage response.''; PubMedEurope PMCScholia
Lin DH, Stuwe T, Schilbach S, Rundlet EJ, Perriches T, Mobbs G, Fan Y, Thierbach K, Huber FM, Collins LN, Davenport AM, Jeon YE, Hoelz A.; ''Architecture of the symmetric core of the nuclear pore.''; PubMedEurope PMCScholia
Kamitani T, Kito K, Nguyen HP, Fukuda-Kamitani T, Yeh ET.; ''Characterization of a second member of the sentrin family of ubiquitin-like proteins.''; PubMedEurope PMCScholia
Messner S, Schuermann D, Altmeyer M, Kassner I, Schmidt D, Schär P, Müller S, Hottiger MO.; ''Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator function.''; PubMedEurope PMCScholia
Hendriks IA, D'Souza RC, Yang B, Verlaan-de Vries M, Mann M, Vertegaal AC.; ''Uncovering global SUMOylation signaling networks in a site-specific manner.''; PubMedEurope PMCScholia
Kabachinski G, Schwartz TU.; ''The nuclear pore complex--structure and function at a glance.''; PubMedEurope PMCScholia
Stephan AK, Kliszczak M, Morrison CG.; ''The Nse2/Mms21 SUMO ligase of the Smc5/6 complex in the maintenance of genome stability.''; PubMedEurope PMCScholia
van Wijk SJ, Müller S, Dikic I.; ''Shared and unique properties of ubiquitin and SUMO interaction networks in DNA repair.''; PubMedEurope PMCScholia
Wu N, Kong X, Ji Z, Zeng W, Potts PR, Yokomori K, Yu H.; ''Scc1 sumoylation by Mms21 promotes sister chromatid recombination through counteracting Wapl.''; PubMedEurope PMCScholia
Saitoh N, Uchimura Y, Tachibana T, Sugahara S, Saitoh H, Nakao M.; ''In situ SUMOylation analysis reveals a modulatory role of RanBP2 in the nuclear rim and PML bodies.''; PubMedEurope PMCScholia
Kamitani T, Kito K, Nguyen HP, Wada H, Fukuda-Kamitani T, Yeh ET.; ''Identification of three major sentrinization sites in PML.''; PubMedEurope PMCScholia
Fontoura BM, Blobel G, Matunis MJ.; ''A conserved biogenesis pathway for nucleoporins: proteolytic processing of a 186-kilodalton precursor generates Nup98 and the novel nucleoporin, Nup96.''; PubMedEurope PMCScholia
Fu et al. (2005) report that only lysine-160 is conjugated to SUMO3. Gong and Yeh (2006) report that lysine-65, lysine-160, and lysine-490 are conjugated to SUMO3.
PIAS1,4 SUMOylate BRCA1 with SUMO2,3 (Galanty et al. 2009, Morris et al. 2009, Vialter et al. 2011, Hendriks et al. 2014). More SUMO2,3-BRCA1 than SUMO1-BRCA1 is observed in vivo (Morris et al. 2009, Galanty et al. 2009). SUMOylation with SUMO2,3 increases in response to oxidative stress (Vialter et al. 2011). SUMOylation of BRCA1 increases its ubiquitin ligase activity (Morris et al. 2009).
PIAS1,4 SUMOylate BRCA1 with SUMO1 at lysine-109 (Morris et al. 2009, Xu et al. 2009). SUMOylation occurs in response to genotoxic stress and double-strand breaks to which PIAS1 and PIAS4 are recruited (Galanty et al. 2009). SUMOylation enhances the ability of BRCA1 to bind and modulate ESR1 (ERalpha) transcriptional activity (Xu et al. 2009). More SUMO2:BRCA1 than SUMO1:BRCA1 is observed in vivo (Morris et al. 2009, Galanty et al. 2009).
RANBP2 of the nuclear pore complex SUMOylates SP100 with SUMO2 at lysine-297 (Tatham et al. 2005, Hendriks et al. 2014). RANBP2 binds UBE2I (UBC9) to facilitate the transfer of SUMO2 from SUMO2:UBE2I to SP100 (Tatham et al. 2005).
UBE2I (UBC9) alone and in association with HDAC7 can SUMOylate PML with SUMO1 at lysine-65, lysine-160, and lysine-490 (Sternsdorf et al. 1997, Kamitani et al. 1998, Duprez et al. 1999, Knipscheer et al. 2008). SUMOylated PML is observed during interphase but not during mitosis (Everett et al. 1999). Knockdown of HDAC7 reduces the number of PML bodies (Gao et al. 2008).
RANBP2 SUMOylates SP100 with SUMO1 at lysine-297 (Pichler et al. 2002, Tatham et al. 2005). RANBP2 has a binding site for SUMO1 and a binding site for UBE2I (UBC9) which may recruit the SUMO1:UBE2I (SUMO1:UBC9) complex (Tatham et al. 2005). RANBP2 is located on the cytoplasmic filaments of the nuclear pore so that SUMOylation may occur during nuclear import of SP100 (Pichler et al. 2002)
RANBP2 of the nuclear pore complex SUMOylates PML with SUMO2 at lysine-65, lysine-160, and lysine-490 (Kamitani et al. 1998, Tatham et al. 2005). RANBP2 contains both a binding site for SUMO1 and a binding site for UBE2I (Tatham et al. 2005). The binding site for UBE2I participates in SUMOylation of PML with SUMO2. SUMO2 colocalizes significantly with PML bodies (Vertegaal et al. 2004).
PML is observed to be SUMOylated with SUMO3 at lysine-65, lysine-160, and lysine-490 (Kamitani et al. 1998). SUMO3 is almost identical with SUMO2 therefore the same E3 ligase (RANBP2) that SUMOylate PML with SUMO2 may also be active with SUMO3, but this has not been proven. PML colocalizes with SUMO3 in nuclear bodies and disruption of SUMO3 expression reduces the number of nuclear bodies (Fu et al. 2005).
The NSMCE2 (NSE2, MMS21) subunit of the SMC5/6 complex SUMOylates the RAD21 and STAG2 subunits of cohesin with SUMO1 (Potts et al. 2006 supplementary data, reviewed in Stephan et al 2011). RAD21 (SCC1) is SUMOylated at several lysines (Wu et al. 2012). SUMOylation of RAD21 occurs during DNA damage repair and is necessary for sister chromatid recombination (Wu et al. 2012).
PIAS4 SUMOylates PARP1 at lysine-203 and lysine-486 with SUMO1 (Martin et al. 2009, Matafora et al. 2009, Messner et al. 2009, Zilio et al. 2013, Impens et al. 2014). SUMOylation abrogates acetylation of PARP1 by p300 (Messner et al. 2009). PARP1 reciprocally poly(ADP-ribose)ylates PIAS4 (Martin et al. 2009). PARP1 is SUMOylated in response to heat shock and SUMOylation is required for full activation of the HSP70.1 promoter (Martin et al 2009).
RPA1 (RPA70) is SUMOylated at lysine-449 and lysine-577 with SUMO2,3 (Dou et al. 2010, Tammsalu et al. 2014). SUMOylation of RPA1 recruits RAD51 to sites of DNA damage to initiate repair through homologous recombination.
TDG is SUMOylated at lysine-330 with SUMO1 by UBE2I (Hardeland et al. 2002, Baba et al. 2005, Steinacher et al. 2005, Knipscheer et al. 2008, Smet-Nocca et al. 2011). Conjugation of SUMO1 to TDG induces dissociation of TDG from its product, an abasic site, and increases turnover of TDG with G:U substrate but abolishes activity with G:T substrate (Hardeland et al. 2002).
PIAS4 SUMOylates RNF168 at an unknown lysine residue (Danielsen et al. 2012). Both RNF168 and HERC2 are SUMOylated at double-strand breaks in DNA. SUMOylation of RNF168 is required for its retention at double-strand breaks.
PIAS4 SUMOylates HERC2 at an unknown lysine residue with SUMO1 (Danielsen et al. 2012). HERC2 binds SUMO1 and is then SUMOylated. SUMOylation of HERC2 promotes binding to RNF8 at double-strand breaks in DNA.
TDG is SUMOylated at lysine-330 with SUMO2,3 by UBE2I and perhaps another E3 ligase (Hardeland et al. 2002, Baba et al. 2006, Hendriks et al. 2014, Tammsalu et al. 2014). SUMOylation increases turnover of TDG with G:U substrate and abolishes activity with G:T substrate (Hardeland et al. 2002).
PIAS4 SUMOylates PARP1 at lysine-203 and lysine-486 with SUMO2,3 in response to heat shock (Martin et al. 2009, Lamoliatte et al. 2013, Hendriks et al. 2014, Tammsalu et al. 2014). PARP1 reciprocally poly(ADP-ribose)ylates PIAS4 (Martin et al. 2009). SUMOylation of PARP1 is required for full activation of the HSP70.1 promoter (Martin et al. 2009).
CDKN2A (p14-ARF) SUMOylates WRN at lysine-356, lysine-496, and lysine-898 with SUMO1 (Woods et al. 2004). SUMOylation of WRN causes it to be released from the nucleolus.
PIAS1,2-1 SUMOylate XRCC4 at lysine-210 with SUMO1 (Yurchenko et al. 2006). SUMOylation causes localization of XRCC4 to the nucleus. (An unSUMOylatable mutant of XRCC4 is localized to the cytosol.)
BLM is SUMOylated at lysine-317, lysine-331, lysine-344, and lysine-347 with SUMO2,3 (Eladad et al. 2005, Zhu et al. 2008, Ouyang et al. 2009, Ouyang et al. 2013, Hendriks et al. 2014). SUMOylation causes BLM to localize to PML bodies (Eladad et al. 2005). SUMOylated BLM recruits RAD51, which directly binds SUMO, and facilitates the substitution of RAD51 for RPA at stalled replication forks (Ouyang et al. 2009, 2013).
CBX4 (Pc2) in the PRC1 complex SUMOylates CETN2 at an unknown residue with SUMO2,3 (Klein and Nigg 2009). SUMOylation of CETN2 enhances its nuclear localization. Interaction with XPC is also required for nuclear localization of CETN2.
XPC is SUMOylated at lysine-655 with SUMO1 (Wang et al. 2005, 2007). SUMOylation occurs after UV irradiation and may target XPC for destruction (Wang et al. 2007).
MDC1 is SUMOylated at lysine-1840 with SUMO2,3 (Luo et al. 2012, Hendriks et al. 2014, Tammsalu et al. 2014). SUMOylation is required for degradation of MDC1. SUMOylation of MDC1 is required for recruitment of RNF4 (Yin et al. 2012), which is believed to ubiquitinylate MDC1, resulting in degradation of MDC1.
MDC1 is SUMOylated at lysine-1840 with SUMO1. SUMOyation of MDC1 is required for its degradation, which is thought to be directed by ubiquitinylation by RNF4 (Luo et al. 2012).
RANBP2 of the nuclear pore complex SUMOylates PML with SUMO1 at lysine-65, lysine-160, and lysine-490 (Sternsdorf et al. 1997, Kamitani et al. 1998, Duprez et al. 1999). SUMOylated PML is observed during interphase but not during mitosis (Everett et al. 1999). RANBP2 contains both a binding site for SUMO1 and a binding site for UBE2I (Tatham et al. 2005). The binding site for SUMO1 may play a role in SUMOylation of PML with SUMO1. Knockdown of RANBP2 reduces the number of PML bodies (Saitoh et al. 2006).
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