Chromatin is the natural substrate for DNA transactions in eukaryotic cells. Studies from the past two decades have shown that chromatin can be modified through ATP-dependent chromatin remodeling and histone modification. Although the role of chromatin remodeling in transcription has been well established, its involvement in other DNA transactions, such as DNA repair, checkpoint regulation and replication is relatively unclear. We and others have shown that the evolutionarily conserved INO80 chromatin remodeling complex is directly involved in double strand break (DSB) repair, checkpoint regulation, as well as DNA replication. Despite the initial characterization, the precise mechanisms by which INO80 participates in these distinct processes remain unclear. INO80 can be recruited to a conventional DSB through its interaction with phosphorylated H2A (3-H2AX). The Nhp10 subunit of INO80 is required for this interaction, suggesting that INO80 can employ a specific subunit to target its function to conventional DSB repair. Recently, we have also shown that INO80 is involved in checkpoint regulation through Mec1/Tel1 phosphorylation of its Ies4 subunit. However, the specific functions of Ies4 phosphorylation in DNA replication and intra-S phase checkpoint remain to be elucidated. Moreover, INO80 has also been implicated in DNA replication recently, and our preliminary studies suggest that INO80 plays a specific role in DNA damage tolerance during replication. The distinct involvement of a single complex in multiple DNA transactions suggests that INO80 utilizes sophisticated regulatory mechanisms in genome maintenance. We hypothesize that INO80 is a key regulator of genome maintenance and employs distinct mechanisms to target and participate in DNA repair, checkpoint regulation and DNA replication. The main goal of our proposal is to test this hypothesis by dissecting the mechanisms of INO80 in distinct processes involved in genome maintenance. We will reveal the mechanism of Ies4 phosphorylation in replication and checkpoint regulation, determine the mechanism targeting INO80 to replication and elucidate the mechanism of INO80 function in DNA damage tolerance. These studies will provide significant new insights into how chromatin remodeling is involved in fundamental biological processes such as DNA repair and replication. Given that defects in DNA replication and repair can cause genome instability and cancer, our study may reveal new mechanisms for tumorigenesis and provide potential novel targets for cancer detection and treatment.
Project Narrative DNA is packaged into chromatin in eukaryotic cells and chromatin must be remodeled to allow DNA replication and repair. Defects in DNA replication and repair cause mutations and can lead to human diseases such as cancer. This grant proposal addresses the novel functions and mechanisms of chromatin remodeling complexes in DNA replication and repair, and will provide potential new targets for cancer detection and treatment.
|Shen, Jianfeng; Ju, Zhenlin; Zhao, Wei et al. (2018) ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med 24:556-562|
|Klages-Mundt, Naeh L; Kumar, Ashok; Zhang, Yuexuan et al. (2018) The Nature of Actin-Family Proteins in Chromatin-Modifying Complexes. Front Genet 9:398|
|Guo, Dong-Chuan; Duan, Xue-Yan; Regalado, Ellen S et al. (2017) Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease. Am J Hum Genet 100:21-30|
|Kapoor, Prabodh; Shen, Xuetong (2016) Stringing Nucleosome Necklaces in the Yeast Genome. Cell 167:600-601|
|Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan et al. (2016) Structure of the intact ATM/Tel1 kinase. Nat Commun 7:11655|
|Kapoor, Prabodh; Bao, Yunhe; Xiao, Jing et al. (2015) Phosphorylation-Dependent Enhancement of Rad53 Kinase Activity through the INO80 Chromatin Remodeling Complex. Mol Cell 58:863-9|
|Kapoor, Prabodh; Bao, Yunhe; Xiao, Jing et al. (2015) Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex. Genes Dev 29:591-602|
|Kapoor, Prabodh; Shen, Xuetong (2014) Mechanisms of nuclear actin in chromatin-remodeling complexes. Trends Cell Biol 24:238-46|
|Kapoor, Prabodh; Chen, Mingming; Winkler, Duane David et al. (2013) Evidence for monomeric actin function in INO80 chromatin remodeling. Nat Struct Mol Biol 20:426-32|
|Falbo, Karina B; Shen, Xuetong (2012) Function of the INO80 chromatin remodeling complex in DNA replication. Front Biosci (Landmark Ed) 17:970-5|
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