A non-canonical function of topoisomerase II in disentangling dysfunctional telomeres.
The decatenation activity of topoisomerase II (Top2), which is widely conserved within the eukaryotic domain, is essential for chromosomal segregation in mitosis. It is less clear, however, whether Top2 performs the same function uniformly across the whole genome, and whether all its functions rely on decatenation. In the fission yeast, Schizosaccharomyces pombe, telomeres are bound by Taz1, which promotes smooth replication fork progression through the repetitive telomeric sequences. Hence, replication forks stall at taz1 Delta telomeres. This leads to telomeric entanglements at low temperatures (<or=20 degrees C) that cause chromosomal segregation defects and loss of viability. Here, we show that the appearance of entanglements, and the resulting cold sensitivity of taz1 Delta cells, is suppressed by mutated alleles of Top2 that confer slower catalytic turnover. This suppression does not rely on the decatenation activity of Top2. Rather, the enhanced presence of reaction intermediates in which Top2 is clamped around DNA, promotes the removal of telomeric entanglements in vivo, independently of catalytic cycle completion. We propose a model for how the clamped enzyme-DNA complex promotes proper chromosomal segregation.
Germe
Thomas
T
Telomere Biology Laboratory, Cancer Research, London, UK.
Miller
Kyle
K
Cooper
Julia Promisel
JP
D000483:Alleles; D002384:Catalysis; D002875:Chromosomes / Q000648:ultrastructure; D004247:DNA / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000737:chemistry*; D019281:Dimerization; D004926:Escherichia coli / Q000378:metabolism; D007438:Introns; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D012568:Schizosaccharomyces / Q000201:enzymology* / Q000235:genetics; D016615:Telomere / Q000648:ultrastructure*; D013696:Temperature
D004247:DNA; D004250:DNA Topoisomerases, Type II
EMBO J. 2005 Sep 7;24(17):3128-35
16096639
J Biol Chem. 1989 Mar 15;264(8):4412-6
2538443
J Biol Chem. 1982 May 25;257(10):5866-72
6279616
EMBO J. 1989 Dec 20;8(13):3997-4006
2556260
Genes Dev. 2004 Sep 15;18(18):2249-54
15371339
Mol Cell. 2009 Mar 13;33(5):559-69
19285940
Mol Cell. 2008 Jul 25;31(2):153-65
18657499
J Biol Chem. 1983 Dec 25;258(24):15365-70
6317692
Cell. 1996 Dec 13;87(6):1103-14
8978614
Curr Biol. 2001 Oct 16;11(20):1624-30
11676925
Cell. 1980 Aug;21(1):103-14
6250706
Proc Natl Acad Sci U S A. 1977 Nov;74(11):4937-41
270727
J Biol Chem. 1998 Apr 17;273(16):9586-92
9545289
J Biol Chem. 1993 Jul 5;268(19):14250-5
8390987
Proc Natl Acad Sci U S A. 1984 May;81(9):2616-20
6326134
Nature. 2006 Apr 6;440(7085):824-8
16598261
Mol Cell. 2003 Feb;11(2):303-13
12620220
Cell. 1985 Jun;41(2):553-63
2985283
Cell. 1984 Nov;39(1):223-32
6091913
J Cell Biol. 1992 Jun;117(5):921-34
1315785
Nature. 1997 Feb 20;385(6618):744-7
9034194
Cell. 1991 Jan 11;64(1):137-48
1846085
Cell. 1980 Jun;20(2):461-7
6248247
Nature. 1987 Mar 26-Apr 1;326(6111):414-6
2436053
Cell. 1980 Aug;21(1):115-25
6250707
Mol Cell. 2001 Jan;7(1):55-63
11172711
Mol Cell. 2004 Jan 16;13(1):7-18
14731390
Cell. 2005 Dec 2;123(5):787-801
16325575
J Biol Chem. 2004 Jul 2;279(27):28100-5
15123716
Cell. 1977 Nov;12(3):817-28
922894
Cell. 1987 Sep 11;50(6):917-25
3040264
Curr Opin Genet Dev. 2008 Apr;18(2):212-20
18407488
Genes Dev. 2007 Aug 1;21(15):1921-36
17671091
Cell. 1980 Mar;19(3):697-707
6244895