The long-term goal of this proposal is to understand the fundamental biophysical properties that link the human MutS homologues (MSH) and MutL homologues (MLH/PMS) to their essential role(s) in signaling mismatch repair (MMR) and/or damage-induced apoptosis. During the last granting period we made considerable progress in our studies of the biochemistry, genetics, cell biology, and tumor biology of the human MMR system. Our studies have detailed the breadth of MSH recognition/activation as well as the distinct role(s) of the MLH/PMS proteins in these processes. Moreover, we appear to have discovered a common DNA signature that underpins the ubiquitous recognition properties of MSH proteins. In this two-year bridge application, we propose to focus on the ATP/ADP-dependent allosteric control within and between human MSH proteins that discriminate their function(s) in either MMR or damage-induced apoptosis. We also propose to examine the effect of novel well-defined human chromatin substrates on MSH and MLH/PMS function(s). These goals will be accomplished by the following Specific Aims: I.) Examine the essential conformational transition(s) that link hMSH2-hMSH6 and hMSH2-hMSH3 ATP-dependent function(s) to MMR initiation and/or Apoptotic signaling, and II.) To detail the effect of defined chromatin substrates on MSH function(s). These studies are designed to draw from the unique biophysical strengths of this laboratory toward a detailed understanding of MSH and MLH/PMS adenosine nucleotide function(s) and dysfunction(s) in MMR, apoptosis, and tumorigenesis. Insight into these processes should contribute to our understanding of ABC and GHKL NTPases as well as aid therapeutics, therapeutic sensitization, and chemoprevention protocols for HNPCC-related tumors.

Public Health Relevance

- Public Health Defects in the human mismatch repair (MMR) genes are the cause of Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and are altered in 10-40% of sporadic colon, endometrial, ovarian, brain, skin, and upper urinary tract tumors. We intend to detail the biophysical processes that drive the MMR proteins into repair or damage-induced apoptosis. Understanding the communication and control process(es) between MMR proteins has important implications for manipulating MMR, damage-induced G2 arrest, apoptosis, tumorigenesis, and ultimately therapeutic intervention.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Molecular Genetics A Study Section (MGA)
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Okano, Paul
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Ohio State University
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Liu, Jiaquan; Hanne, Jeungphill; Britton, Brooke M et al. (2016) Cascading MutS and MutL sliding clamps control DNA diffusion to activate mismatch repair. Nature 539:583-587
Fishel, Richard; Heinen, Christopher D (2016) Enhanced gene targeting to evaluate Lynch syndrome alterations. Proc Natl Acad Sci U S A 113:3918-20
Jeon, Yongmoon; Kim, Daehyung; Martín-López, Juana V et al. (2016) Dynamic control of strand excision during human DNA mismatch repair. Proc Natl Acad Sci U S A 113:3281-6
Spies, Maria; Fishel, Richard (2015) Mismatch repair during homologous and homeologous recombination. Cold Spring Harb Perspect Biol 7:a022657
Liu, Jiaquan; Hanne, Jeungphill; Britton, Brooke M et al. (2015) An Efficient Site-Specific Method for Irreversible Covalent Labeling of Proteins with a Fluorophore. Sci Rep 5:16883
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Senavirathne, Gayan; Liu, Jiaquan; Lopez Jr, Miguel A et al. (2015) Widespread nuclease contamination in commonly used oxygen-scavenging systems. Nat Methods 12:901-2
Honda, Masayoshi; Okuno, Yusuke; Hengel, Sarah R et al. (2014) Mismatch repair protein hMSH2-hMSH6 recognizes mismatches and forms sliding clamps within a D-loop recombination intermediate. Proc Natl Acad Sci U S A 111:E316-25
Lee, Jong-Bong; Cho, Won-Ki; Park, Jonghyun et al. (2014) Single-molecule views of MutS on mismatched DNA. DNA Repair (Amst) 20:82-93
Martín-López, Juana V; Fishel, Richard (2013) The mechanism of mismatch repair and the functional analysis of mismatch repair defects in Lynch syndrome. Fam Cancer 12:159-68

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