Regulation of ATP‐dependent Chromatin Remodeling

Abstract

The objective of our research is to understand how ATP‐dependent chromatin remodeling machines (Remodelers) are regulated. Remodelers contain a catalytic ATPase subunit that conducts DNA translocation, used to pump DNA around the nucleosome. Here, we define and characterize new domains/regions present on the ATPases of the RSC and ISWI remodelers, and show how they regulate ATPase, translocase and nucleosome remodeling activities.The catalytic ATPase of the RSC remodeler is bound by a heterodimer of actin‐related proteins (ARPs). Here, we present a crystal structure of the ARP module at high resolution. In order to understand how ARPs regulate DNA translocation, we applied genetic, biophysical and biochemical approaches. Here, we reveal a new domain that functions as a negative regulator, restricting ATPase and DNA translocation activities, which is antagonized by the ARP/HSA module. For ISWI remodelers, we reveal an autoinhibition mechanism for ISWI regulation involving an N‐terminal domain, and also define a novel region in the C‐terminus of the ISWI enzyme important for the coupling of energy‐consumption with DNA translocation. Together, these discoveries emphasize the importance of the regulation of ATPase, translocase and remodeling activities by an elaborate network of domains. This work is supported by NIH GM60415 and HHMI.