Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

Heinen, Christopher D.; Cyr, Jennifer L.; Cook, Christopher; Punja, Nidhi; Sakato, Miho; Forties, Robert A.; Martín-López, Juana; Hingorani, Manju; Fishel, Richard

doi:10.1074/jbc.m111.297523

Cited by 34 publications

(51 citation statements)

References 38 publications

(39 reference statements)

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“…S4 and Fig. S9) consistent with the previous studies using SPR or TIRF system (14,18,42). These results suggest that the mismatch processing during replication-coupled MMR is likely to be more efficient than heteroduplex rejection that blocks homeologous recombination.…”

Section: Discussionsupporting

confidence: 81%

“…This observation suggests that ATP may induce a transient conformation of hMSH2-hMSH6 that has reduced mismatch-binding activity. Indeed, ATPγS increases the k on ∼20-fold, suggesting that the hMSH2-hMSH6 must undergo complete hydrolysis of the bound ATP into the mismatch binding competent ADP-bound form, as proposed by previous studies (42).…”

Section: Hmsh2-hmsh6 Sliding Clamp Is Constrained Within the D-loop Butmentioning

confidence: 66%

“…To facilitate surface tethering, the C terminus of hMSH2 was modified to include a BirA recognition sequence that allows covalent incorporation of a biotin moiety (bio-hMSH2-hMSH6). The biohMSH2-hMSH6 was expressed in Sf9 insect cells with the E. coli BirA, and the biotinylated heterodimer was purified as previously described (42). The bio-hMSH2-hMSH6 retained mismatched DNA binding activity comparable with that of the untagged protein (Fig.…”

Section: Hmsh2-hmsh6 Sliding Clamp Is Constrained Within the D-loop Butmentioning

confidence: 99%

“…The EC 50 •ATP = 5.9 ± 0.1 μM). It is important to note that the EC 50 for ATP and ATPγS serve as an indicator of sliding-clamp stability on DNA and account for a multistep process that starts with the ADP-ATP exchange by the mismatch-bound clamp and leads to the formation of the sliding clamp, and its subsequent dissociation promoted by ATP hydrolysis (21,41,42).…”

Section: Hmsh2-hmsh6 Sliding Clamp Is Constrained Within the D-loop Butmentioning

confidence: 99%

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Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Honda

Okuno

Hengel

et al. 2014

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

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High fidelity homologous DNA recombination depends on mismatch repair (MMR), which antagonizes recombination between divergent sequences by rejecting heteroduplex DNA containing excessive nucleotide mismatches. The hMSH2-hMSH6 heterodimer is the first responder in postreplicative MMR and also plays a prominent role in heteroduplex rejection. Whether a similar molecular mechanism underlies its function in these two processes remains enigmatic. We have determined that hMSH2-hMSH6 efficiently recognizes mismatches within a D-loop recombination initiation intermediate. Mismatch recognition by hMSH2-hMSH6 is not abrogated by human replication protein A (HsRPA) bound to the displaced single-stranded DNA (ssDNA) or by HsRAD51. In addition, ATP-bound hMSH2-hMSH6 sliding clamps that are essential for downstream MMR processes are formed and constrained within the heteroduplex region of the D-loop. Moreover, the hMSH2-hMSH6 sliding clamps are stabilized on the Dloop by HsRPA bound to the displaced ssDNA. Our findings reveal similarities and differences in hMSH2-hMSH6 mismatch recognition and sliding-clamp formation between a D-loop recombination intermediate and linear duplex DNA.

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Section: Discussionsupporting

confidence: 81%

Section: Hmsh2-hmsh6 Sliding Clamp Is Constrained Within the D-loop Butmentioning

confidence: 66%

Section: Hmsh2-hmsh6 Sliding Clamp Is Constrained Within the D-loop Butmentioning

confidence: 99%

Section: Hmsh2-hmsh6 Sliding Clamp Is Constrained Within the D-loop Butmentioning

confidence: 99%

See 2 more Smart Citations

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Honda

Okuno

Hengel

et al. 2014

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

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“…78,79 These observations were collectively taken to suggest that MSH2 may be yet another damage-associated molecular pattern recognized by Vc9Vd2 T cells. An overlooked point worth considering is the fact that MSH2 also has an intrinsic ability to bind and hydrolyze ATP, 80 which may be the property providing the common mechanism leading to the mobilization of human peripheral blood cd T cells. Both ATP synthase/F1-ATPase and MSH2 are evolutionarily conserved molecules that serve essential stress-sensitive homeostatic functions in prokaryotes and eukaryotes and can bind nucleotide derivatives, and this may confer the potential to present low molecular weight pAgs to Vc9Vd2 T cells' clever immunosurveillance strategy.…”

Section: Vd2 T Cells: To Know the Complex Burden Of Being Humanmentioning

confidence: 99%

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

2012

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The elusive task of defining the character of cd T cells has been an evolving process for immunologists since stumbling upon their existence during the molecular characterization of the a and b T cell receptor genes of their better understood brethren. Defying the categorical rules used to distinctly characterize lymphocytes as either innate or adaptive in nature, cd T cells inhabit a hybrid world of their own. At opposing ends of the simplified spectrum of modes of antigen recognition used by lymphocytes, natural killer and ab T cells are particularly well equipped to respond to the 'missing self' and the 'dangerous non-self', respectively. However, between these two reductive extremes, we are chronically faced with the challenge of making peace with the 'safe non-self' and dealing with the inevitable 'distressed self', and it is within this more complex realm cd T cells excel thanks to their highly empathetic nature. This review gives an overview of the latest insights revealing the unfolding story of human cd T cells, providing a biographical sketch of these unique lymphocytes in an attempt to capture the essence of their fundamental nature and events that influence their life trajectory. What hangs in their balance is their nuanced ability to differentiate the friends from the foe and the pathological from the benign to help us adapt swiftly and efficiently to life's many stresses. Keywords: antigen recognition; danger-associated molecular patterns; gamma delta T cell subsets; immune homeostasis; innate immunity; stress response PROLOGUE Since the time of their accidental discovery during the molecular characterization of the a and b T cell receptor (TCR) genes belonging to their relatively unambiguous brethren, 1 'enigmatic' is still one of the most commonly used adjectives to describe cd T cells. This can be attributed to the fact that these unconventional lymphocytes have thus far been remarkably successful in thwarting most attempts at definition. Much of what we know about T cell biology and function comes from what has been discerned through studies done on ab T cells; however, one thing that is certain is that the majority of the rules governing the lives of ab T cells are surprisingly irrelevant when it comes to understanding the elusive character of cd T cells. Table 1 highlights some of the major differences between these two T cell subsets in humans.Recognition by cd T cells is not typically in the context of classical major histocompatibility complex (MHC) class I or II molecules and neither is antigen processing required. 2,3 These observations are corroborated by the fact that the majority of cd T cells are CD8 and CD4 negative. Crystal structure analysis of the cd TCR determined that the length and conformation of cd TCR resemble immunoglobulins (Ig) more than the ab TCR, which was taken to suggest that antigen recognition by cd T cells may be more similar to the binding of antibody to antigen rather than the MHC/peptide complex recognized by ab T cells. 4 The very basis of foreign antigen rec...

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Mismatch Repair

Fishel¹,

Lee²

2016

DNA Replication, Recombination, and Repair

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Human MSH2 (hMSH2) Protein Controls ATP Processing by hMSH2-hMSH6

Cited by 34 publications

References 38 publications

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Mismatch repair protein hMSH2–hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

Mismatch Repair

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