MED1 (MBD4), A Novel Gene Associated with Cancer Drug Resistance

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Background:

Dr. Alfonso Bellacosa and colleagues of the Fox Chase Cancer Center have discovered MED1 (also known as MBD4), a novel human gene involved in the repair of mismatched bases. MED1 codes for a base excision repair enzyme that interacts specifically with the mismatch repair protein MLH1, the human homolog of E. coli mutL. MED1 appears to play an important role in the initiation, progression, and prognosis of a variety of cancers. As reported in the 2003 PNAS article, MED1 mediates the DNA damage response to anticancer agents.

MED1 acts as a thymine and uracil glycosylase specific for G:T and G:U mismatches, and is likely involved in repair at CpG sites. In the absence of MED1 function, unrepaired G:T and G:U mismatches would lead to G:C to A:T transition mutations; these changes at CpG sites are the most frequent mutations in human cancer, including nearly 50% of somatic mutations of the tumor suppressor gene P53 in colorectal cancer.

Mutations in MED1 are also associated with:

• human cancers with microsatellite instability
• resistance to 5fluorouracil (5FU), a major chemotherapeutic agent and the main agent used in the treatment of colorectal cancer.

Development of a MED1 defective mouse by another group has confirmed its association with tumorigenesis.

Research is continuing at Fox Chase Cancer Center to further define the role of MED1 in cancer initiation, progression, and prognosis.

Applications:

• Potential tool for cancer diagnosis and prognosis
• Target for therapeutic intervention both in tumor suppression and in resistance to chemotherapy

Publications:

• Cortellino, S. et al., "The base excision repair enzyme MED1 mediates DNA damage response to antitumor drugs and is associated with mismatch repair system integrity," Proc Natl Acad Sci U S A. (2003); 100(25): 150716
• Bellacosa, A., "Role of MED1 (MBD4) Gene in DNA Repair and Human" Cancer. J. Cellular Physiology (2001); 187: 137144

Patent Status:

U.S. Patent 6,599,700 "Methods for detection of transition single-nucleotide polymorphisms" is issued. An additional U.S. application is pending.

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