Our studies focus on the mechanisms of homologous recombination in humans. The homologous recombination pathway is crucial for maintenance of genome stability. It promotes the repair of the most harmful DNA lesions: DNA double-stranded breaks and inter-strand cross-links. In addition, homologous recombination is important for faithful segregation of homologous chromosomes during meiosis. Deficiencies in homologous recombination lead to cancer, premature aging, and various chromosomal abnormalities such as Down, Klinefelter, and other syndromes.
To achieve accurate repair of DNA double-stranded breaks the homologous recombination machinery uses homologous dsDNA as a template. The unique and evolutionary conserved mechanism of homologous recombination is responsible for recognition of homologous DNA sequences and their pairing. However, the molecular principles of this mechanism remain a mystery. To uncover these principles our lab investigates the biochemical activities of the key homologous recombination proteins including RAD51, its meiosis-specific homologue DMC1, RAD52, RAD54, and others. Using homologous recombination proteins we attempt to reconstitute the process DNA double strand break repair in vitro.
Since the homologous recombination activity is vital for rapidly proliferating cells and may be protective against the killing effect of anti-cancer drugs, we are developing specific small-molecule inhibitors of key homologous recombination proteins. We will use these inhibitors for advancement of novel anti-cancer therapies. In addition, these inhibitors can be used as a probe to analyze the functions of homologous recombination proteins in the cell.
“Polarity and bypass of DNA heterology during branch migration of Holliday junctions by human RAD54, BLM, and RECQ1”
Mazina, OM., Rossi, MJ, Deakyne, JS, Huang, F., and Mazin, AV
J. Biol. Chem. 287, 11820-11832 (2012).
“Inhibition of homologous recombination in human cells by targeting RAD51 recombinase”
Huang, F., Mazina, OM., Zentner, IJ, Cocklin, S., and Mazin, AV.
J. Medicinal Chemistry 55, 3011-3020 (2012). Rated twice as a “must read” by Faculty of 1000.
"The RecA/RAD51 protein drives migration of Holliday junctions via polymerization on DNA. "
Rossi, MJ, Mazina, OM, Bugreev, DV, and Mazin, AV.
Proc Natl Acad Sci USA 108, 6432-6437 (2011).
“The resistance of DMC1 D-loops to dissociation may account for the DMC1 requirement in meiosis”
Bugreev, DV, Pezza, RJ, Mazina, OM, Voloshin, ON, Camerini-Otero RD, and Mazin AV.
Nature Struct. & Mol. Biol., 18, 56-60 (2011).
"Cooperation of RAD51 and RAD54 in regression of a model replication fork."
Bugreev, DV, Rossi, MJ, and Mazin, AV.
Nucleic Acids Res,.39, 2153-2164 (2011). Rated a “must read” by Faculty of 1000.
“Rad54, the motor of homologous recombination”
Mazin, AV, Mazina, OM, Bugreev, DV, Rossi. MJ.
DNA Repair (Amst) 9:286-302 (2010).
“Bloom syndrome helicase stimulates RAD51 DNA strand exchange activity through a novel mechanism”
Bugreev, DV, Mazina, OM, and Mazin, AV
J. Biol. Chem. 284, 26349-26359 (2009).
Human Rad54 protein stimulates human Mus81/Eme1 endonuclease.
Mazina, OM., Mazin, AV
Proc. Natl. Acad. Sci. USA, 105(47): p. 18249-18254 (2008).
"Novel pro- and anti-recombination activities of the Bloom’s syndrome helicase"
Bugreev, DV, Yu, X, Egelman, EH, Mazin, AV
Genes & Development, 21: 3085-3094 (2007).
"Interactions of human Rad54 protein with branched DNA molecules"
Mazina, OM, Rossi, MJ, Thoma, N, and Mazin, AV
J. Biol. Chem., 282 (29): 21068-21080 (2007).
"Rad54 dissociates homologous recombination intermediates by branch migration"
Bugreev, DV, Hanaoka, F, and Mazin, AV
Nature Struct. & Mol. Biol., 14 (8): 746-753 (2007).
"Rad54 protein promotes branch migration of the Holliday junctions"
Bugreev, DV, Mazina, OM, and Mazin, AV
Nature (London). 442: 590-593 (2006). Reviewed by Faculty of 1000 Biology
"Ca2+ activates human homologous recombination protein Rad51 by modulating its ATPase activity"
Bugreev, DV, and Mazin, AV
Proc. Natl. Acad. Sci. USA, 101: 9988-9993 (2004).
"Human Rad54 protein stimulates DNA strand exchange activity of hRad51 protein in the presence of Ca2+"
Mazina, OM, and Mazin, AV
J. Biol. Chem., 279: 52041-52051 (2004). Selected by the JBC editors as a Paper of the Week