| Structural highlights
Function
[EXO1_HUMAN] 5'->3' double-stranded DNA exonuclease which may also possess a cryptic 3'->5' double-stranded DNA exonuclease activity. Functions in DNA mismatch repair (MMR) to excise mismatch-containing DNA tracts directed by strand breaks located either 5' or 3' to the mismatch. Also exhibits endonuclease activity against 5'-overhanging flap structures similar to those generated by displacement synthesis when DNA polymerase encounters the 5'-end of a downstream Okazaki fragment. Required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Essential for male and female meiosis.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
Human exonuclease 1 (hExo1) plays important roles in DNA repair and recombination processes that maintain genomic integrity. It is a member of the 5' structure-specific nuclease family of exonucleases and endonucleases that includes FEN-1, XPG, and GEN1. We present structures of hExo1 in complex with a DNA substrate, followed by mutagenesis studies, and propose a common mechanism by which this nuclease family recognizes and processes diverse DNA structures. hExo1 induces a sharp bend in the DNA at nicks or gaps. Frayed 5' ends of nicked duplexes resemble flap junctions, unifying the mechanisms of endo- and exonucleolytic processing. Conformational control of a mobile region in the catalytic site suggests a mechanism for allosteric regulation by binding to protein partners. The relative arrangement of substrate binding sites in these enzymes provides an elegant solution to a complex geometrical puzzle of substrate recognition and processing.
Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family.,Orans J, McSweeney EA, Iyer RR, Hast MA, Hellinga HW, Modrich P, Beese LS Cell. 2011 Apr 15;145(2):212-23. PMID:21496642[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Qiu J, Qian Y, Chen V, Guan MX, Shen B. Human exonuclease 1 functionally complements its yeast homologues in DNA recombination, RNA primer removal, and mutation avoidance. J Biol Chem. 1999 Jun 18;274(25):17893-900. PMID:10364235
- ↑ Lee BI, Wilson DM 3rd. The RAD2 domain of human exonuclease 1 exhibits 5' to 3' exonuclease and flap structure-specific endonuclease activities. J Biol Chem. 1999 Dec 31;274(53):37763-9. PMID:10608837
- ↑ Genschel J, Bazemore LR, Modrich P. Human exonuclease I is required for 5' and 3' mismatch repair. J Biol Chem. 2002 Apr 12;277(15):13302-11. Epub 2002 Jan 24. PMID:11809771 doi:http://dx.doi.org/10.1074/jbc.M111854200
- ↑ Lee Bi BI, Nguyen LH, Barsky D, Fernandes M, Wilson DM 3rd. Molecular interactions of human Exo1 with DNA. Nucleic Acids Res. 2002 Feb 15;30(4):942-9. PMID:11842105
- ↑ Sun X, Zheng L, Shen B. Functional alterations of human exonuclease 1 mutants identified in atypical hereditary nonpolyposis colorectal cancer syndrome. Cancer Res. 2002 Nov 1;62(21):6026-30. PMID:12414623
- ↑ Sharma S, Sommers JA, Driscoll HC, Uzdilla L, Wilson TM, Brosh RM Jr. The exonucleolytic and endonucleolytic cleavage activities of human exonuclease 1 are stimulated by an interaction with the carboxyl-terminal region of the Werner syndrome protein. J Biol Chem. 2003 Jun 27;278(26):23487-96. Epub 2003 Apr 18. PMID:12704184 doi:http://dx.doi.org/10.1074/jbc.M212798200
- ↑ Genschel J, Modrich P. Mechanism of 5'-directed excision in human mismatch repair. Mol Cell. 2003 Nov;12(5):1077-86. PMID:14636568
- ↑ Nielsen FC, Jager AC, Lutzen A, Bundgaard JR, Rasmussen LJ. Characterization of human exonuclease 1 in complex with mismatch repair proteins, subcellular localization and association with PCNA. Oncogene. 2004 Feb 19;23(7):1457-68. PMID:14676842 doi:http://dx.doi.org/10.1038/sj.onc.1207265
- ↑ Dzantiev L, Constantin N, Genschel J, Iyer RR, Burgers PM, Modrich P. A defined human system that supports bidirectional mismatch-provoked excision. Mol Cell. 2004 Jul 2;15(1):31-41. PMID:15225546 doi:http://dx.doi.org/10.1016/j.molcel.2004.06.016
- ↑ Doherty KM, Sharma S, Uzdilla LA, Wilson TM, Cui S, Vindigni A, Brosh RM Jr. RECQ1 helicase interacts with human mismatch repair factors that regulate genetic recombination. J Biol Chem. 2005 Jul 29;280(30):28085-94. Epub 2005 May 9. PMID:15886194 doi:http://dx.doi.org/10.1074/jbc.M500265200
- ↑ Zhang Y, Yuan F, Presnell SR, Tian K, Gao Y, Tomkinson AE, Gu L, Li GM. Reconstitution of 5'-directed human mismatch repair in a purified system. Cell. 2005 Sep 9;122(5):693-705. PMID:16143102 doi:http://dx.doi.org/10.1016/j.cell.2005.06.027
- ↑ Wilson DM 3rd, Carney JP, Coleman MA, Adamson AW, Christensen M, Lamerdin JE. Hex1: a new human Rad2 nuclease family member with homology to yeast exonuclease 1. Nucleic Acids Res. 1998 Aug 15;26(16):3762-8. PMID:9685493
- ↑ Orans J, McSweeney EA, Iyer RR, Hast MA, Hellinga HW, Modrich P, Beese LS. Structures of human exonuclease 1 DNA complexes suggest a unified mechanism for nuclease family. Cell. 2011 Apr 15;145(2):212-23. PMID:21496642 doi:10.1016/j.cell.2011.03.005
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