NDLI: A novel and unified two-metal mechanism for DNA cleavage by type II and IA topoisomerases

Content Provider	PubMed Central
Author	Schmidt, Bryan H. Burgin, Alex B. Deweese, Joseph E. Osheroff, Neil Berger, James M.
Abstract	Type II topoisomerases are required for the management of DNA tangles and supercoils1, and are targets of clinical antibiotics and anti-cancer agents2. These enzymes catalyze the ATP-dependent passage of one DNA duplex (the transport or T-segment) through a transient, double-stranded break in another (the gate or G-segment), navigating DNA through the protein using a set of dissociable internal interfaces, or “gates”3,4. For more than 20 years, it has been established that a pair of dimer-related tyrosines, together with divalent cations, catalyze G-segment cleavage5–7. Recent efforts have proposed that strand scission relies on a “two-metal mechanism”8–10, a ubiquitous biochemical strategy that supports vital cellular processes ranging from DNA synthesis to RNA self-splicing11,12. Here we present the structure of the DNA-binding and cleavage core of Saccharomyces cerevisiae topo II covalently linked to DNA through its active-site tyrosine at 2.5 Å resolution, revealing for the first time the organization of a cleavage-competent type II topoisomerase configuration. Unexpectedly, metal-soaking experiments indicate that cleavage is catalyzed by a novel variation of the classic two-metal approach. Comparative analyses extend this scheme to explain how distantly-related type IA topoisomerases cleave single-stranded DNA, unifying the cleavage mechanisms for these two essential enzyme families. The structure also highlights a hitherto undiscovered allosteric relay that actuates a molecular “trapdoor” to prevent subunit dissociation during cleavage. This connection illustrates how an indispensable chromosome-disentangling machine auto-regulates DNA-breakage to prevent the aberrant formation of mutagenic and cytotoxic genomic lesions.
Related Links	http://dx.doi.org/10.1038/nature08974
Ending Page	644
Page Count	4
Starting Page	641
File Format	PDF
ISSN	00280836
e-ISSN	14764687
Journal	Nature
Issue Number	7298
Volume Number	465
Language	English
Publisher Date	2010-06-03
Access Restriction	Open
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
5	Website/Portal (Helpdesk)	Queries regarding NDLI and its services	support@ndl.gov.in
6	Contents and Copyright Issues	Queries related to content curation and copyright issues	content@ndl.gov.in
7	National Digital Library of India Club (NDLI Club)	Queries related to NDLI Club formation, support, user awareness program, seminar/symposium, collaboration, social media, promotion, and outreach	clubsupport@ndl.gov.in
8	Digital Preservation Centre (DPC)	Assistance with digitizing and archiving copyright-free printed books	dpc@ndl.gov.in
9	IDR Setup or Support	Queries related to establishment and support of Institutional Digital Repository (IDR) and IDR workshops	idr@ndl.gov.in

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