Geeta Narlikar

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  Mechanisms of Chromatin Remodeling Motors
  Geeta Narlikar
  The chromatin state of a gene helps encode the regulatory information that controls its expression. ATP-dependent chromatin-remodeling motors catalyze the changes in chromatin structure that are required for both rapid exposure and long-term occlusion of DNA sites. The mechanisms by which these motors function however, are not well understood. The challenges in studying chromatin-remodeling motors are intimately linked to the complex nature of their task. Even the smallest movement of the histone octamer across DNA requires a highly coordinated process of breaking and reforming the many histone-DNA contacts. We have developed quantitative approaches to study chromatin-specific conformational changes. These methods have allowed us to apply conceptual advances from established motor fields to discover mechanistic features that are unique to chromatin-remodeling motors. An illustrative example is our work on ACF, the main chromatin remodeling complex involved in generating the evenly spaced nucleosomes required to generate condensed chromatin structures. We have found that ACF functions as dimeric motor in which the two ATPases face each other and take turns to engage either side of a nucleosome. This dimeric motor mechanism differs from that of other dimeric motors studied to date, such as kinesin and dimeric helicases, whose biological functions require translocation along a uniform polymeric substrate. The biological functions of chromatin remodeling enzymes like ACF appear to have placed very different demands on motor architecture. While kinesin and other dimeric motors studied to date use two motors facing in the same direction to processively move in one direction, the opposing polarity of the two motors in ACF enables ACF to rapidly and processively change the direction of nucleosome movement in order to achieve a defined spacing.