Areas of Interest
Colon cancer is the third most common malignancy in men and
women and ranks behind only lung cancer in cancer deaths. The
most common hereditary disease that predisposes patients to
colorectal cancer is hereditary non-polyposis colon cancer (HNPCC)
which stems from mutations in the mismatch repair (MMR) genes.
In addition to its role in HNPCC, flawed MMR has been implicated
in 15-40% of sporadic colorectal and other extracolonic tumors
indicating a more general role for MMR in tumor protection.
Although many functional details of the MMR proteins have
emerged, the mechanism by which flawed MMR contributes to
tumorigenesis is not fully understood. Faulty MMR results in an
elevated mutation rate (mutator phenotype), which has been
proposed to lead to an accumulation of oncogene and tumor
suppressor mutations that ultimately cause cancer. More recent
work has revealed that MMR proteins play an important role in
cell cycle arrest and apoptosis in response to certain DNA
damaging agents. Thus, MMR mutations may affect tumorigenesis
through multiple mechanisms. Our laboratory is interested in
understanding what functions of the MMR system are affected
during tumorigenesis.
We are addressing this broad question through a multi-pronged
approach. First, we are examining how the biochemical and
biophysical properties of MMR proteins are affected by
cancer-associated missense mutations. Missense mutations of at
least two MMR genes hMSH2 and hMSH6 have been linked to HNPCC
families providing a tool whereby full-length proteins with
single amino acid alterations can be studied to determine how
these alterations affect function. The hMSH2 and hMSH6 proteins
form heterodimers in cells that recognize DNA lesions and
initiate the repair process. Our laboratory utilizes purified
human hMSH2-hMSH6 heterodimers in a series of in vitro
biochemical and biophysical assays to learn about the normal
biochemical mechanism as well as the consequences of
cancer-associated mutations on this mechanism. Secondly, we are
examining the cellular functions of the MMR proteins and the
effects of cancer-causing missense mutations by studying how
these mutant proteins perform in DNA repair, cell cycle
checkpoint signaling, apoptosis signaling and other functional
assays. Finally, we are interested in identifying proteins that
interact with the normal MMR proteins and in determining how
these interactions are affected during tumorigenesis.
Lab Rotation Projects
The research in my laboratory involves an array of techniques
from biochemistry to cell biology to animal models to address
the fundamental question of why mutations in DNA mismatch repair
genes cause cancer. We are predominantly interested in using
cancer-associated missense mutations of the hMSH2 and hMSH6
genes to understand the functions of mismatch repair affected
during colorectal tumorigenesis. Projects include:
- Biochemical and biophysical characterizations of the
wild-type and mutant hMSH2-hMSH6 heterodimers…
- Using cell culture models to study the functions of
mutant hMSH2 and hMSH6 in damage repair and response...
- Examining the pre-neoplastic colorectal lesions aberrant
crypt foci for defects in mismatch repair...
Other projects available and can be discussed depending on
student’s interest.
Selected Publications
Cyr, JL and Heinen, CD. Hereditary cancer-associated missense
mutations in hMSH6 uncouple ATP hydrolysis from DNA mismatch
binding. 2008. Journal of Biological Chemistry. 283:31641-31648.
Rosenberg, DW, Yang, S, Pleau, DC, Greenspan, EJ, Stevens, RG,
Rajan, TV, Heinen, CD, Levine, J and O’Brien, MJ. Mutations in
BRAF and KRAS differentially distinguish serrated vs.
non-serrated hyperplastic aberrant crypt foci in humans. 2007.
Cancer Research. 67:3551-3554.
Greenspan, EJ, Cyr, JL, Pleau, DC, Levine, J, Rajan, TV,
Rosenberg, DW and Heinen, CD. Microsatellite instability in
aberrant crypt foci from patients without concurrent colon
cancer. 2007. Carcinogenesis. 28:769-776.
Stevens, RG, Swede, H, Heinen, CD, Jablonski, M, Grupka, M,
Ross, B, Parente, M, Tirnauer, JS, Giardina, C, Rajan, TV,
Rosenberg, DW and Levine, J. Aberrant Crypt Foci in patients
with a positive family history of sporadic colorectal cancer.
2007. Cancer Letters. 248:262-268.
Shim K-S, Tombline, G, Heinen CD, Charbonneau, N, Schmutte,
C, Fishel R. Magnesium influences the discrimination and release
of ADP by human RAD51. 2006. DNA Repair. 5:704-717.
Shim K-S, Schmutte C, Tombline G, Heinen CD, Fishel R. hXRCC2
enhances ADP/ATP processing and strand exchange by hRAD51. 2004.
Journal of Biological Chemistry. 279:30385-30394.
Heinen CD, Schmutte C, Fishel R. DNA repair and tumorigenesis:
lessons from hereditary cancer syndromes. 2002. Cancer Biology
and Therapy 1:477-485.
Heinen CD, Wilson T, Mazurek A, Berardini M, Butz C, Fishel
R. HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6
molecular switch functions. 2002. Cancer Cell 1:469-478.
Heinen CD, Goss KH, Cornelius JR, Babcock GF, Knudsen ES,
Kowalik T, Groden J. The APC tumor suppressor controls entry
into S-phase through its ability to regulate the cyclin D/RB
pathway. 2002. Gastroenterology 123:751-763*.
*Accompanying commentary available in same issue.
rev. 1-09 |
