Genomic instability contributes largely to the development of human cancers. This is why cells have a variety of mechanisms that detect and repair DNA lesions that could result in permanent and deleterious genetic changes. The small ubiquitin-related modifier (SUMO) plays a key role in regulating cellular processes linked to the maintenance of genome integrity, with cells deficient in components of the SUMO pathway displaying defects in DNA replication, DNA repair and chromosome segregation. Although many DNA replication and repair factors have been identified in recent years as substrates for SUMO modification, the exact molecular mechanisms by which SUMO modification exerts its effects on these proteins remain poorly understood.
Dr. Matunis and his colleagues have recently shown that SUMO-2 modification regulates the trafficking of one DNA repair protein—the Bloom’s syndrome DNA helicase (BLM)—between promyelocytic leukemia (PML) nuclear bodies and DNA damage-induced foci. Based on their preliminary studies, the researchers hypothesize that SUMO-2 modification functions as a general mechanism for controlling DNA replication and repair proteins by regulating their dynamic distribution between PML nuclear bodies and sites of DNA damage.
McLaughlin D, Coey CT, Yang WC, Drohat AC, Matunis MJ. "Characterizing requirements for small ubiquitin-like modifier (sumo) modification and binding on base excision repair activity of thymine-DNA glycosylase in vivo." J Biol Chem. 2016 Apr 22;291(17):9014-24. doi: 10.1074/jbc.M115.706325. Epub 2016 Feb 25.
Reiter KH, Ramachandran A, Xia X, Boucher LE, Bosch J, Matunis MJ. "Characterization and structural insights into selective E1-E2 interactions in the human and plasmodium falciparum SUMO conjugation systems." J Biol Chem. 2016 Feb 19;291(8):3860-70. doi: 10.1074/jbc.M115.680801. Epub 2015 Dec 23.
Zhang K, Donnelly CJ, Haeusler AR, Grima JC, Machamer JB, Steinwald P, Daley EL, Miller SJ, Cunningham KM, Vidensky S, Gupta S, Thomas MA, Hong I, Chiu SL, Huganir RL, Ostrow LW, Matunis MJ, Wang J, Sattler R, Lloyd TE, Rothstein JD. "The C9orf72 repeat expansion disrupts nucleocytoplasmic transport." Nature. 2015 Sep 3;525(7567):56-61. doi: 10.1038/nature14973. Epub 2015 Aug 26.
Cubeñas-Potts C, Srikumar T, Lee C, Osula O, Subramonian D, Zhang XD, Cotter RJ, Raught B, Matunis MJ. "Identification of SUMO-2/3-modified proteins associated with mitotic chromosomes." Proteomics. 2015 Feb;15(4):763-72. doi: 10.1002/pmic.201400400. Epub 2015 Jan 7.
Guzzo CM, Ringel A, Cox E, Uzoma I, Zhu H, Blackshaw S, Wolberger C, Matunis MJ. "Characterization of the SUMO-binding activity of the myeloproliferative and mental retardation (MYM)-type zinc fingers in ZNF261 and ZNF198." PLoS One. 2014 Aug 18;9(8):e105271. doi: 10.1371/journal.pone.0105271. eCollection 2014.
Wiener R, DiBello AT, Lombardi PM, Guzzo CM, Zhang X, Matunis MJ, Wolberger C. "E2 ubiquitin-conjugating enzymes regulate the deubiquitinating activity of OTUB1." Nat Struct Mol Biol. 2013 Sep;20(9):1033-9. doi: 10.1038/nsmb.2655. Epub 2013 Aug 18.
Zhu J, Zhu S, Guzzo CM, Ellis NA, Sung KS, Choi CY, Matunis MJ. "Small ubiquitin-related modifier (SUMO) binding determines substrate recognition and paralog-selective SUMO modification." J Biol Chem. 2008 Oct 24;283(43):29405-15. doi: 10.1074/jbc.M803632200. Epub 2008 Aug 15.
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." Hum Mol Genet. 2005 May 15;14(10):1351-65. Epub 2005 Apr 13.
Bernier-Villamor V, Sampson DA, Matunis MJ, Lima CD. "Structural basis for E2-mediated SUMO conjugation revealed by a complex between ubiquitin-conjugating enzyme Ubc9 and RanGAP1." Cell. 2002 Feb 8;108(3):345-56.
Sampson DA, Wang M, Matunis MJ. "The small ubiquitin-like modifier-1 (SUMO-1) consensus sequence mediates Ubc9 binding and is essential for SUMO-1 modification." J Biol Chem. 2001 Jun 15;276(24):21664-9. Epub 2001 Mar 19.