Abstract
Many cellular pathways are dedicated to maintain the integrity of the genome. In eukaryotes, the underlying DNA transactions occur in the context of chromatin. Cells utilize chromatin and its dynamic nature to regulate those genome integrity pathways. Accordingly, chromatin becomes restructured and modified around DNA damage sites. Here, we review the current knowledge of a chromatin remodeler Fun30SMARCAD1, which plays a key role in genome maintenance. Fun30SMARCAD1 promotes DNA end resection and the repair of DNA double-stranded breaks (DSBs). Notably, however, Fun30SMARCAD1 plays additional roles in maintaining heterochromatin and promoting transcription. Overall, Fun30SMARCAD1 is involved in distinct processes and the specific roles of Fun30SMARCAD1 at DSBs, replication forks and sites of transcription appear discordant at first view. Nonetheless, a picture emerges in which commonalities within these context-dependent roles of Fun30SMARCAD1 exist, which may help to gain a more global understanding of chromatin alterations induced by Fun30SMARCAD1.
Highlights
We review the current knowledge of a chromatin remodeler Fun30SMARCAD1, which plays a key role in genome maintenance
Fun30SMARCAD1 is involved in distinct processes and the specific roles of Fun30SMARCAD1 at double-stranded breaks (DSBs), replication forks and sites of transcription appear discordant at first view
Past research has given us very valuable insights into the individual functions of Fun30SMARCAD1, but is there commonality or can we link them to a specific enzymatic activity? The most obvious commonality at least between the function during DNA end resection and the function in the maintenance of silent chromatin regions during DNA replication is that both DNA end resection and DNA replication involve the formation of ssDNA and eviction of nucleosomes
Summary
CUE domains are known for their ability to bind ubiquitin (Donaldson et al, 2003; Kang et al, 2003; Shih et al, 2003), and the N-terminal CUE domain in SMARCAD1 was shown to mediate interactions with the chromatin regulator KAP1 (Rowbotham et al, 2011; Ding et al, 2018; Lim et al, 2019). The SMARCAD1-KAP1 interaction has very recently been shown to occur between the SMARCAD1 Nterminal CUE domain and a specific patch in KAP1 that does structurally not resemble ubiquitin (Lim et al, 2019) This finding suggests alternative and still-to-be explored interaction modes of Fun30SMARCAD1. Nucleosome remodelers use ATP to remodel histone-DNA contacts in order to move or position nucleosomes, evict them or change their composition (Clapier and Cairns, 2009; Hargreaves and Crabtree, 2011) These molecular activities can be studied well in vitro and analogous experiments have been performed for Fun (Awad et al, 2010; Adkins et al, 2013, 2017). We aim to summarize the known functions, and to highlight commonalities, since a common model describing Fun function would help discriminate direct from indirect consequences of a loss of Fun function and facilitate future research
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