Mms22p protects Saccharomyces cerevisiae from DNA damage induced by topoisomerase II.
The cleavage reaction of topoisomerase II, which creates double-stranded DNA breaks, plays a central role in both the cure and initiation of cancer. Therefore, it is important to understand the cellular processes that repair topoisomerase II-generated DNA damage. Using a genome-wide approach with Saccharomyces cerevisiae, we found that Deltamre11, Deltaxrs2, Deltarad50, Deltarad51, Deltarad52, Deltarad54, Deltarad55, Deltarad57 and Deltamms22 strains were hypersensitive to etoposide, a drug that specifically increases levels of topoisomerase II-mediated DNA breaks. These results confirm that the single-strand invasion pathway of homologous recombination is the major pathway that repairs topoisomerase II-induced DNA damage in yeast and also indicate an important role for Mms22p. Although Deltamms22 strains are sensitive to several DNA-damaging agents, little is known about the function of Mms22p. Deltamms22 cultures accumulate in G2/M, and display an abnormal cell cycle response to topoisomerase II-mediated DNA damage. MMS22 appears to function outside of the single-strand invasion pathway, but levels of etoposide-induced homologous recombination in Deltamms22 cells are lower than wild-type. MMS22 is epistatic with RTT101 and RTT107, genes that encode its protein binding partners. Finally, consistent with a role in DNA processes, Mms22p localizes to discrete nuclear foci, even in the absence of etoposide or its binding partners.
Baldwin
E L
EL
Department of Biochemistry, Vanderbilt University School of Medicine Nashville, TN 37232-0146, USA.
Berger
A C
AC
Corbett
A H
AH
Osheroff
N
N
D002453:Cell Cycle; D002467:Cell Nucleus / Q000737:chemistry; D044842:Cullin Proteins / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D005047:Etoposide / Q000633:toxicity; D017353:Gene Deletion; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D044842:Cullin Proteins; C497133:Mms22 protein, S cerevisiae; C476451:RTT101 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005047:Etoposide; D004250:DNA Topoisomerases, Type II
Annu Rev Biochem. 2001;70:369-413
11395412
Chem Res Toxicol. 1993 Sep-Oct;6(5):585-97
8292734
Curr Opin Struct Biol. 2002 Feb;12(1):115-22
11839498
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16934-9
12482937
Nature. 2003 Jan 23;421(6921):436-40
12540918
Curr Top Med Chem. 2003;3(3):321-38
12570766
Genes Cells. 2003 May;8(5):465-80
12694535
Mol Cell. 2003 May;11(5):1323-36
12769855
Mutat Res. 2004 Mar;566(2):131-67
15164978
Genes Dev. 2000 Jan 1;14(1):81-96
10640278
Prog Nucleic Acid Res Mol Biol. 2000;64:221-53
10697411
Trends Genet. 2000 Jun;16(6):259-64
10827453
Mutat Res. 2000 Jun 30;451(1-2):71-89
10915866
Biochemistry. 2001 Jan 23;40(3):712-8
11170388
Trends Genet. 2001 Apr;17(4):214-21
11275327
Med Pediatr Oncol. 2001 May;36(5):525-35
11340607
Genes Dev. 2001 Nov 1;15(21):2809-21
11691833
Nat Genet. 2001 Dec;29(4):426-34
11726929
Genetics. 2001 Dec;159(4):1449-65
11779788
Nat Cell Biol. 2003 Jun;5(6):572-7
12766777
J Biol Chem. 2003 Jun 20;278(25):22828-37
12676951
Mol Cell. 2003 Jul;12(1):221-32
12887907
Nucleic Acids Res. 2003 Aug 1;31(15):4373-84
12888496
Nat Biotechnol. 2004 Jan;22(1):62-9
14661025
EMBO J. 2004 Mar 10;23(5):1188-97
14988729
Curr Opin Cell Biol. 2004 Jun;16(3):328-34
15145359
Biochemistry. 2004 Jun 15;43(23):7563-74
15182198
J Biol Chem. 1983 Jul 10;258(13):8421-8
6305984
J Biol Chem. 1983 Dec 25;258(24):15365-70
6317692
Proc Natl Acad Sci U S A. 1988 Oct;85(20):7501-5
2845409
Biochemistry. 1989 Jul 25;28(15):6229-36
2551367
Cancer Res. 1989 Nov 15;49(22):6365-8
2553254
Methods Enzymol. 1991;194:281-301
2005793
J Biol Chem. 1992 Jul 5;267(19):13150-3
1320012
Cancer Res. 1992 Aug 15;52(16):4467-72
1322791
Cancer Res. 1993 Jan 1;53(1):89-93
8380128
Nature. 1993 Apr 22;362(6422):709-15
8469282
Annu Rev Pharmacol Toxicol. 1994;34:191-218
8042851
Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12031-5
7991579
J Biol Chem. 1995 Sep 1;270(35):20359-64
7657608
Nature. 1996 Jan 18;379(6562):225-32
8538787
Mol Cell Biol. 1996 May;16(5):2164-73
8628283
Annu Rev Biochem. 1996;65:635-92
8811192
Yeast. 1996 Jun 30;12(8):773-86
8813764
Cancer Causes Control. 1996 Nov;7(6):581-90
8932918
Adv Pharmacol. 1994;29B:127-43
8996605
Drug Metab Rev. 1998 May;30(2):285-304
9606605
Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8733-8
9671747
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):63-81
9748506
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):139-54
9748545
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):195-211
9748575
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):213-22
9748584
Biochim Biophys Acta. 1998 Oct 1;1400(1-3):233-55
9748598
Q Rev Biophys. 1998 May;31(2):107-44
9794033
Int J Cancer Suppl. 1998;11:26-8
9876473
Annu Rev Genet. 1998;32:495-519
9928489
J Clin Oncol. 1999 Feb;17(2):569-77
10080601
Microbiol Mol Biol Rev. 1999 Jun;63(2):349-404
10357855
Science. 1999 Aug 6;285(5429):901-6
10436161
Genes Dev. 1999 Aug 15;13(16):2159-76
10465792
Nature. 2002 Jan 10;415(6868):180-3
11805837