DNA Replication and Repair

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We have solved X-ray crystal structures of the FAM111A serine protease domain (SPD). The structural information will help us determine potential mechanisms that regulate the protease activity of FAM111A. Our biochemical and structural studies suggested that FAM111A SPD forms a homodimer through the alpha-1 helix at the N-terminus, where two subunits are held together through hydrophobic interactions. We found that substitution of valine on the dimerization interface with aspartate disrupted dimer formation and diminished its protease activity. These data suggest that the dimerization of the enzyme domain is crucial for the activity of FAM111A. Supporting the importance of the dimer formation, our in vivo experiments suggested that the monomeric mutant was defective in preventing DPC accumulation and failed to promote DNA replication at DPCs induced by camptothecin. These results raise a new concept that chemicals that can block dimer formation could be used as an inhibitor of FAM111A.