Binding of Mismatched Microsatellite DNA Sequences by the Human MSH2 Protein

Fishel, Richard; Ewel, Amy; Lee, Suman; Lescoe, Mary Kay; Griffith, Jack D.

doi:10.1126/science.7973733

Cited by 167 publications

(84 citation statements)

References 36 publications

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“…In this case, some form of post replication repair will be needed to correct the error. It has been previously shown that the human homologue of E. coli MutS, hMSH2, can bind to duplex oligonucleotides containing short (5-16 nucleotides) insertion/deletion loops (30). This repair protein has also been demonstrated to bind PCNA (29,67).…”

Section: Figmentioning

confidence: 99%

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Dynamics of β and Proliferating Cell Nuclear Antigen Sliding Clamps in Traversing DNA Secondary Structure

Yao¹,

Hurwitz²,

O’Donnell³

2000

Journal of Biological Chemistry

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Chromosomal replicases of cellular organisms utilize a ring shaped protein that encircles DNA as a mobile tether for high processivity in DNA synthesis. These "sliding clamps" have sufficiently large linear diameters to encircle duplex DNA and are perhaps even large enough to slide over certain DNA secondary structural elements. This report examines the Escherichia coli ␤ and human proliferating cell nuclear antigen clamps for their ability to slide over various DNA secondary structures. The results show that these clamps are capable of traversing a 13-nucleotide ssDNA loop, a 4-base pair stem-loop, a 4-nucleotide 5 tail, and a 15-mer bubble within the duplex. However, upon increasing the size of these structures (20-nucleotide loop, 12-base pair stemloop, 28-nucleotide 5 tail, and 20-nucleotide bubble) the sliding motion of the ␤ and proliferating cell nuclear antigen over these elements is halted. Studies of the E. coli replicase, DNA polymerase III holoenzyme, in chain elongation with the ␤ clamp demonstrate that upon encounter with an oligonucleotide annealed in its path, it traverses the duplex and resumes synthesis on the 3 terminus of the oligonucleotide. This sliding and resumption of synthesis occurs even when the oligonucleotide contains a secondary structure element, provided the ␤ clamp can traverse the structure. However, upon encounter with a downstream oligonucleotide containing a large internal secondary structure, the holoenzyme clears the obstacle by strand displacing the oligonucleotide from the template. Implications of these protein dynamics to DNA transactions are discussed.

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Section: Figmentioning

confidence: 99%

“…PCNA is also thought to interact with human homologues of E. coli MutS and MutL (hMSH-2 and hMLH1, respectively; (29)). hMSH2 specifically binds single base pair mismatches as well as short loops of 4 -16 nucleotides (30,31). Other proteins that interact with PCNA include DNA ligase I (32), Xeroderma pigmentosum G (33), and p21 (Cip1) (34,35).…”

mentioning

confidence: 99%

Dynamics of β and Proliferating Cell Nuclear Antigen Sliding Clamps in Traversing DNA Secondary Structure

Yao¹,

Hurwitz²,

O’Donnell³

2000

Journal of Biological Chemistry

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“…Small loops, bulges, or kinked DNA occur frequently in DNA, and provide signals for p53 recognition (4-7), recombination (8,9), and/or most often removal by the mismatch repair system (10)(11)(12)(13)(14). Two heterodimeric mismatch recognition complexes, MSH2/MSH6 and MSH2/MSH3, operate in mammals with distinct, but overlapping specificities (12)(13)(14).…”

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confidence: 99%

Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Lang

Coats

Majka

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Insertion and deletion of small heteroduplex loops are common mutations in DNA, but why some loops are prone to mutation and others are efficiently repaired is unknown. Here we report that the mismatch recognition complex, MSH2/MSH3, discriminates between a repair-competent and a repair-resistant loop by sensing the conformational dynamics of their junctions. MSH2/MSH3 binds, bends, and dissociates from repair-competent loops to signal downstream repair. Repair-resistant Cytosine-Adenine-Guanine (CAG) loops adopt a unique DNA junction that traps nucleotide-bound MSH2/MSH3, and inhibits its dissociation from the DNA. We envision that junction dynamics is an active participant and a conformational regulator of repair signaling, and governs whether a loop is removed by MSH2/MSH3 or escapes to become a precursor for mutation.

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“…A highlight was the demonstration with Arnold Levine at Princeton University that p53 binds to bulged bases and Holliday junctions (39), a possibility that came out of our studies of RecA protein binding to DNA containing bulged bases (40). Work on mismatch repair has involved ongoing collaborations with Paul Modrich at Duke University (41,42), Richard Kolodner at the University of California, San Diego (43,44), and Rick Fishel at Ohio State University (45,46), where these methods have revealed the binding of mismatch repair factors to DNA, as well as DNA looping by MutS (42). These studies paralleled work on the binding of key factors in signal transduction between sites of damage and the damage response pathways with Aziz Sancar at the University of North Carolina (47,48).…”

Section: Visualizing Proteins That Bind To Unusual Dna Structuresmentioning

confidence: 99%

Many Ways to Loop DNA

Griffith

2013

Journal of Biological Chemistry

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In the 1960s, I developed methods for directly visualizing DNA and DNA-protein complexes using an electron microscope. This made it possible to examine the shape of DNA and to visualize proteins as they fold and loop DNA. Early applications included the first visualization of true nucleosomes and linkers and the demonstration that repeating tracts of adenines can cause a curvature in DNA. The binding of DNA repair proteins, including p53 and BRCA2, has been visualized at three-and four-way junctions in DNA. The trombone model of DNA replication was directly verified, and the looping of DNA at telomeres was discovered.

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Binding of Mismatched Microsatellite DNA Sequences by the Human MSH2 Protein

Cited by 167 publications

References 36 publications

Dynamics of β and Proliferating Cell Nuclear Antigen Sliding Clamps in Traversing DNA Secondary Structure

Dynamics of β and Proliferating Cell Nuclear Antigen Sliding Clamps in Traversing DNA Secondary Structure

Conformational trapping of Mismatch Recognition Complex MSH2/MSH3 on repair-resistant DNA loops

Many Ways to Loop DNA

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