Posttranslational modifications play a key role in recruiting chromatin remodeling and modifying enzymes to specific regions of chromosomes to modulate chromatin structure. Alc1 (amplified in liver cancer 1), a member of the SNF2 ATPase superfamily with a carboxy-terminal macrodomain, is encoded by an oncogene implicated in the pathogenesis of hepatocellular carcinoma. Here we show that Alc1 interacts transiently with chromatin-associated proteins, including histones and the poly(ADP-ribose) polymerase Parp1. Alc1 ATPase and chromatin remodeling activities are strongly activated by Parp1 and its substrate NAD and require an intact macrodomain capable of binding poly(ADP-ribose). Alc1 is rapidly recruited to nucleosomes in vitro and to chromatin in cells when Parp1 catalyzes PAR synthesis. We propose that poly(ADPribosyl)ation of chromatin-associated Parp1 serves as a mechanism for targeting a SNF2 family remodeler to chromatin.Alc1 ͉ chromatin remodeling enzyme ͉ macrodomain ͉ poly-(ADP-ribose) polymerase ͉ Snf2-like ATPase I n eukaryotic cells, chromosomal DNA is packaged into nucleosomes, which are in turn folded into higher order nucleosome arrays in chromatin fibers. This packaging allows the Ϸ2 m of DNA that make up the human genome to fit into nuclei with diameters on the order of 2-6 m; however, it also blocks access to DNA of the machinery responsible for transcription, replication, and DNA repair. Eukaryotic organisms have evolved a set of chromatin modifying and remodeling enzymes that alter the structure of chromatin to control accessibility to the machineries responsible for DNA replication and repair and for transcription. These enzymes have been shown to be targeted to regions of modified chromatin by such domains as bromodomains, which can bind acetylated histones, or chromodomains, tudor domains, or MBT domains, which can interact with methylated histones (1-4).ALC1 (amplified in liver cancer 1), alternatively known as CHD1L, is a member of the SNF2 superfamily of ATPases, some of which function as chromatin remodeling enzymes (5-7). Sequence alignments suggest that Alc1 is similar to chromatin remodeling ATPases Snf2, Iswi, and Chd1, which have been implicated in transcription, DNA repair, and replication (7). Alc1 lacks identifiable chromo-, bromo-, tudor-, MBT, or other domains known to have chromatin targeting functions. Instead, it contains a carboxy-terminal macrodomain. Macrodomains have been shown through biochemical and structural analyses to bind ADP-ribose (8).Over 50% of human hepatocellular carcinoma (HCC) patients contain a chromosomal amplification at 1q21, which includes the ALC1 gene (9-11). Alc1-overexpressing cells exhibit increased colony formation in soft agar and increased tumorigenicity in nude mice (11), suggesting that ALC1 functions as an oncogene.While mounting evidence points to a potential role for Alc1 in oncogenesis, the molecular function of the Alc1 ATPase has not been studied. Here, we show that Alc1 is a chromatin remodeling enzyme that is recruited to nucleosom...

The mammalian Tip49a and Tip49b proteins belong to an evolutionarily conserved family of AAA ؉ ATPases. In Saccharomyces cer- The related mammalian Tip49a and Tip49b proteins are members of a family of AAA ϩ (associated with various cellular activities) ATPases with roles in DNA repair, recombination, and transcriptional regulation (1, 2). In Saccharomyces cerevisiae, the Tip49a and Tip49b proteins (also known as Rvb1 and Rvb2) participate in chromatin remodeling as subunits of the multiprotein SWR1 and INO80 ATP-dependent chromatin remodeling complexes (3-5). The SWR1 complex remodels chromatin by catalyzing ATP-dependent replacement of H2A-H2B histone dimers in nucleosomes by dimers containing histone variant Htz1 (referred to as H2AZ in mammalian cells) (3). In addition to Tip49a and Tip49b, the SWR1 complex includes the SNF2 family helicase Swr1, actin-related proteins Arp4 and Arp6, YEATS domain family member Yaf9, bromodomain protein Bdf1, and additional proteins Swc3-Swc7, which are of unknown function (3-5).The INO80 complex catalyzes ATP-dependent sliding of nucleosomes along DNA and, based on genetic and other evidence, may be involved in the repair of DNA double strand breaks and in transcriptional regulation (6 -12). The INO80 complex includes Tip49a and Tip49b, the SNF2 family helicase Ino80, actin-related proteins Arp4, Arp5, and Arp8, YEATS domain family member Taf14, HMG (high mobility group) domain protein Nhp10, and six additional proteins designated Ies1-Ies6 (6, 13). Thus, the SWR1 and INO80 complexes share three proteins (Tip49a, Tip49b, and Arp4) and contain additional homologous components. In addition, each of the two complexes has a number of unique subunits.The orthologs of the Tip49a and Tip49b AAA ϩ ATPases also play roles in chromatin remodeling in higher eukaryotes. Tip49a and Tip49b are subunits of the mammalian and Drosophila melanogaster TRRAP-TIP60 histone acetyltransferase (HAT) 3 complexes (14 -17). In addition to Tip49a and Tip49b, the TRRAP-TIP60 complex includes ATM/ phosphatidylinositol 3-kinase family member TRRAP, the SNF2 family p400 or Domino helicase, actin-related protein Arp4, bromodomaincontaining protein BRD8, the enhancer of polycomb (EPC) and/or enhancer of polycomb-like (EPC-like) protein, inhibitor of growth 3 (ING3), DNA methyltransferase 1-associated protein (DMAP1), MRG15 and/or the related MRGX protein, the MRGBP protein, and TIP60, a HAT belonging to the MYST family. Characterization of the activities associated with the higher eukaryotic TRRAP-TIP60 complex revealed that it possesses HAT activity similar to that of the S. cerevisiae NuA4 HAT complex, which acetylates histones H2A and H4 (reviewed in Ref. 18). The human and D. melanogaster TRRAP-TIP60 complexes were found to play critical roles in double-stranded DNA break repair (16,17). Notably, the D. melanogaster TRRAP-TIP60 complex is capable of acetylating nucleosomal phospho-H2Av and replacing it with unmodified H2Av, indicating that in flies this single complex performs functions closely related t...