Discovery of DNA repair mechanisms: A summary of the findings behind the 2015 Nobel Prize in Chemistry

Recently, the Nobel Assembly announced the winners of the 2015 Nobel Prize in Chemistry. The award is focused around the discovery of three different mechanisms behind DNA repair. Tomas Lindahl was awarded one third of the prize for his work on base excision repair. Paul Modrich awarded one third of the prize for studies on mismatch repair. Aziz Sancar was also awarded one third of the prize for his discovery of nucleotide excision repair.

Tomas Lindahl initially started his research career by finding that DNA has limited chemical stability, partially due to spontaneous chemical reactions that occur on DNA bases. Lindahl identified E. coli uracil-DNA glycosylase and 3-methyladenine glycosylase, two proteins involved in base excision repair. In the following years, he outlined a model detailing how DNA glycosylases recognize and cleave the base-deoxyribose glycosyl bonds of damaged nucleotides, flip and release the nucleotide, and then facilitate its replacement by other enzymes, including endonuclease, DNA polymerase, and DNA ligase.

Paul Modrich was one of the first scientists to provide direct evidence for mismatch repair. Modrich also developed an assay to allow analysis of DNA mismatch repair in E. coli using bacteriophage heteroduplexes with mismatches that could be recognized by two different restriction endonucleases. With this assay, he showed that repair activity was ATP-dependent, indicated heteroduplex methylation states, and highlighted how mutations in mutH, mutL, mutS, and mutD impair mismatch repair. Later, Modrich explored further variations in mismatch repair using other cellular models and studying how the process differs on leading versus lagging DNA strands.

Aziz Sancar followed up on previous theories regarding repair mechanisms that correct UV-induced lesions by identifying proteins involved in these processes. Sancar developed a technique that allowed for labeling and detection of proteins encoded by a plasmid of interest in a background free of other components. This technique was used to identify proteins encoded by uvrA, uvrB, and uvrC involved in nucleotide excision repair. Sancar used these proteins to determine several steps in the correcting of UV-induced thymine dimers, one of many lesions recognized and amended by nucleotide excision repair processes.

For more information on the 2015 Nobel Prize in Chemistry, click here.

LKT carries several compounds that alter DNA repair machinery! For more information on these, please click the representative links below.

PARP inhibitors:

• A9612 AZD2461
• O4402 Olaparib
• V1745 Veliparib

ATM/ATR kinase inhibitors:

• C2540 CGK 733

MGMT inhibitors:

• B1855 O6-Benzylguanine
• L5750 Lomeguatrib

References:

Mol CD, Arvai AS, Slupphaug G, et al. Crystal structure and mutational analysis of human uracil-DNA glycosylase: structural basis for specificity and catalysis. Cell. 1995 Mar 24;80(6):869-78. PMID: 7697717.

Lahue RS, Au KG, Modrich P. DNA mismatch correction in a defined system. Science. 1989 Jul 14;245(4914):160-4. PMID: 2665076.

Lu AL, Clark S, Modrich P. Methyl-directed repair of DNA base-pair mismatches in vitro. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4639-43. PMID: 6308634.

Sancar A, Rupp WD. A novel repair enzyme: UVRABC excision nuclease of Escherichia coli cuts a DNA strand on both sides of the damaged region. Cell. 1983 May;33(1):249-60. PMID: 6380755.

Sancar A, Hack AM, Rupp WD. Simple method for identification of plasmid-coded proteins. J Bacteriol. 1979 Jan;139(1):692-3. PMID: 368040.

Lindahl T. New class of enzymes acting on damaged DNA. Nature. 1976 Jan 1-8;259(5538):64-6. PMID: 765833.

Lindahl T. An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci USA. 1974 Sep;71(9):3649-53. PMID: 4610583.