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Regulation of ALC1 (amplified in liver cancer) involves interplay between the SNF2 ATPase domain, PAR binding macrodomain and other conserved elements (563.1)
Author(s) -
Trivedi Rushi,
Gottschalk Aaron,
Conaway Joan,
Conaway Ronald
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.563.1
Subject(s) - aaa proteins , atpase , nucleosome , biology , binding site , dna , chromatin , microbiology and biotechnology , chemistry , biochemistry , enzyme
Regulation of ALC1 (Amplified in Liver Cancer) involves interplay between the SNF2 ATPase domain, PAR binding macrodomain and other conserved elements Rushi D. Trivedi* 1,2 , Aaron J. Gottschalk 1 , Joan W. Conaway 1,2 , Ronald C. Conaway 1,2 1 Stowers Institute for Medical Research, Kansas City, MO; 2 Department of Biochemistry, University of Kansas Medical Center, Kansas City, KS. ALC1, also known as CHD1L, was originally identified as a gene present on a human chromosome 1q21 region amplified in ~50% of human hepatocellular carcinomas. ALC1, a member of the SNF2 family of ATPases, has an N‐terminal SNF2‐like ATPase that is most closely related to that of ISWI, and a C‐terminal macrodomain that binds selectively to poly(ADP‐ribose) (PAR). Between the ATPase and the macrodomain is an evolutionarily conserved region with no clear homology to any known domains. This “linker” region can be further divided into three sub‐regions of greatest conservation. We have previously shown that wild type ALC1 possesses DNA‐dependent ATPase and ATP‐dependent nucleosome remodeling activities that are strongly activated by nucleosome bound PARylated PARP1. A point mutation in the ALC1 macrodomain that interferes with PAR binding prevents PARP1‐ and NAD‐dependent ALC1 activation. Our current line of studies are aimed at investigating the interplay between ALC1 ATPase and macrodomain in the context of nucleosome remodeling. Preliminary results suggest that the SNF2 ATPase of ALC1 is inherently inactive but is activated upon interaction with PARylated PARP. Upon performing an extensive mutagenesis study of the conserved regions within the “linker”, we have identified potential regulatory elements and a putative DNA binding domain that could facilitate the communication between the two domains. Furthermore, we are analyzing the interplay between the SNF2 ATPase, macrodomain, and “linker” by characterizing the activities of chimeric ALC1 constructs with macrodomains exchanged from different proteins. Grant Funding Source : Stowers Institute for Medical Research